Process for the preparation of 6-azido-11beta-hydroxy-4,6-pregnadienes and novel intermediates produced thereby

ABSTRACT

AN IMPROVED PROCESS FOR PREPARING PHARMACOLOGICALLY ACTIVE 6-AZIDO-11B-HYDROXY-4,6-PREGNADIENE-3,20-DIONES COMPRISES PREPARING AN 11B-ACYLOXY DERIVATIVE OF A 6A,7AOXIDO-11B-HYDROXY-4-PREGNENE-3,20-DIONE, SAID 11B-ACYLOXY BEING A MEMBER SELECTED FROM THE GROUP CONSISTING OF 11B-FORMYLOXY-, 11B-ACETOXY- AND 11B-HALOGENOACETOXY-; TREATING SAID 6A,7A-OXIDO-11B-ACYLOXY-4-PREGNENE-3,20DIONE WITH AN ALKALI METAL AZIDE IN A NON-REACTIVE, ORGANIC SOLVENT; TREATING THE THEREBY FORMED 6B-AZIDO-7A-HYDROXY11B-ACYLOXY-4-PREGNENE-3,20-DIONE OR A 7A-ESTER THEREOF WITH CONCENTRATED HYDROCHLORIC ACID IN A LOWER ALKANOIC ACID TOGETHER WITH AN INERT SOLVENT OR, ALTERNATIVELY, TREATING A 7A-ESTER THEREOF WITH A TETRAALKYLAMMONIUM HALIDE IN AN APROTIC SOLVENT, SAID 7A-ESTER BEING EITHER A 7A-LOWER ALKANOATE OR A 7A-HYDROCARBONSULFONATE; FOLLOWED BY HYDROLYSIS OF THE 6-AZIDO-11B-ACYLOXY-4,6-PREGNADIENE-3,20DIONE THEREBY FORMED. IF DESIRED, HYDROLYSIS OF THE 11ACYLOXY MAY BE CARRIED OUT ON THE 6B-AZIDO-7A-HYDROXY11B-ACYLOXY-4-PREGNENE-3,20 DIONE INTERMEDIATE. INTERMEDIATES DESCRIBED AND CLAIMED IN THIS PROCESS ARE 6B-AZIDO-7A-HYDROXY-11!-ACYLOXY-4PREGNENE-3,20DIONES, THE 7A-ESTERS THEREOF AND 6-AZIDO-11B-ACYLOXY-4,6PREGNADIENE-3,20-DIONES.

United States Patent Oflice Patented Dec. 26, 1972 PROCESS FOR THEPREPARATION OF 6-AZIDO- 1I S-HYDROXY-4,6-PREGNADIENES AND NOVELINTERMEDIATES PRODUCED THEREBY Richard C. Rausser, Union, and Elliot L.Shapiro, Cedar Grove, NJ., assignors to Schering Corporation,Bloomfield, NJ. No Drawing. Filed June 15, 1971, Ser. No. 153,405

Int. Cl. C07c 173/10 US. Cl. 260-349 30 Claims ABSTRACT OF THEDISCLOSURE An improved process for preparing pharmacologically activeazido 11fi-liydroxy-4,6-pregnadiene-3,ZO-diones comprises preparing an11 fi-acyloxy derivative of a 604,70;-oxido-l1B-hydroxy-4-pregnene-3,20-dione, said llfl-acyloxy being amember selected from the group consisting of 11 ,B-formyloxy-, 11,B-acetoxyand l1B-halogenoacetoxy-; treating said6a,7a-oxido-l1B-acyloxy-4-pregnene-3,20- dione with an alkali metalazide in a non-reactive, organic solvent; treating the thereby formed6B-azido-7u-hydroxyll{3-acyloxy-4-pregnene-3,20-dione or a 7u-esterthereof with concentrated hydrochloric acid in a lower alkanoic acidtogether with an inert solvent or, alternatively, treating a 7a-esterthereof with a tetraalkylammonium halide in an aprotic solvent, said7oz-6St6l being either a 7a-lower alkanoate or a7a-hydrocarbonsulfonate; followed by hydrolysis of the6-azido-ll,B-acyloxy-4,6-pregnadiene-3,20- dione thereby formed. Ifdesired, hydrolysis of the 11- acyloxy may be carried out on the6fi-azido-7u-hydroxy- 1 lfi-acyloxy-4-pregnene-3,20-dione intermediate.

Intermediates described and claimed in this process are 6 8 azido7a-hydroxy-1lfl-acyloxy-4-pregnene-3,20- diones, the 7a-esters thereofand 6-azido-1lfl-acyloxy-4,6- pregnadiene-3,20-diones.

FIELD OF THE INVENTION This invention relates to an improved process andto novel intermediates produced thereby.

More specifically, this invention relates to an improved process for thepreparation of compositions of matter which may be classified as6-azido-1lB-hydroxy-3,20-diketo-4,6-bis-dehydrosteroids of the pregnaneseries, and to novel intermediates produced thereby.

DESCRIPTION OF THE PRIOR ART Compositions of matter which may beclassified as 6- azido-3,20-diketo-4,6-bis-dehydrosteroids of thepregnane series, methods for their manufacture, and intermediatesproduced thereby are described and claimed in co-pending applicationsSer. Nos. 58,163 and 59,367 filed July 24, 1970 and July 29, 1970,respectively, both of common assignee as the instant application. In US.Ser. No. 58,163 are disclosed 6-azido-6-dehydroprogesterones possessingprogestational activity and in US. Ser. No. 59,367 are disclosed6-azido-4,6-pregnadiene-3,20-diones having a cortical side chain at Cl7which possess glucocorticoid properties, a preferred species of whichare 6-aZido-11, 17,21-trioxygenated 4,6 pregnadienes having enhancedanti-inflammatory activity. Among the preferred compounds claimed inboth the foregoing applications are included6-azido-4,6-pregnadiene-3,20-diones having an 11,8-hydroxyl group.

Both co-pending applications describe a convenient method for preparing6-azido-4,6-pregnadiene-3,20-diones which comprises treating a6a,7a-oxido-4-pregnene-3,20- dione with an alkali metal azide in anon-reative, organic solvent, and treating the thereby formed 6t3-azido-7a-hydroxy-4-pregnene-3,20-dione with concentrated hydrochloricacid in a lower alkanoic acid together with an inert solvent or,alternatively, treating a 7a-ester of said thereby formed6,6-azido-7a-hydroxy-4-pregnene-3,20-dione with a dehydroacyloxylatingagent selected from the group consisting of tetraalkylammonium halide inan aprotic solvent, and concentrated hydrochloric acid in a loweralkanoic acid together with an inert solvent, said 7a-ester being amember selected from the group consisting of a 7a-lower alkanoate havingup to 8 carbon atoms and a 7a-hydrocarbonsulfonate having up to 7 carbonatoms, whereby a 6-azido-4,6-pregnadiene-3,20-dione is formed. Theintermediates in this process, i.e.6fl-azido-7u-hydroxy-4-pregnene-3,20-diones and 7-esters thereof, arealso claimed in the aforenamed co-pending applications.

We have found, when carrying out the above-described process on a6a,7a-oxido-4-pregnene-3,20-dione having an llfi-hydroxyl group, thatthe step of opening the 60,70cepoxide with an alkali metal azide goesvery slowly (thus allowing competing side reactions to occur) and,particularly when there is also a 9a-halogen present, results inextremely poor yields of the 6B-azido-7a,1lfi-dihydroxy- 4-pregneneintermediate. By our invention, We have discovered that when thellfi-hydroxyl group is converted to an ll-lower alkanoate ester(preferably an ll-acetate) prior to treatment of the 6u,7a-epoxide withan alkali metal azide, the reaction rate of the 6u,7a-epoxide openingincreases and there are obtained better yields of desired product inless time and of greater purity than when utilizing the freellfl-hydroxyl steroid as starting compound. Thus, for example,6u,7oz-OXidOhYCllOCOltlSOIlB 11,21-diacetate upon treatment with sodiumazide in aqueous methanol according to this invention yields theoreticalyield of 6fi-azido-7u-hydroxyhydrocortisone 11,21-diacetate in less thanone fifth the time it takes to convert the corresponding ll s-hydroxyintermediate under the same reaction conditions to 68% theoretical yieldof 65-azido-7e-hydroxyhydrocortisone 21-acetate.

The advantageous results of our improved process are particularlybeneficial to an unexpected degree when a 9a-halogeno as well as anllfl-hydroxyl is present in the molecule. Thus,6a,7a-oxido-1,2-dihydrodexamethasone 11,21-diacetate (i.e.6a,7a-oxido-9a-fluoro-16u-methyl-4- pregnene-l1;3,l7a,2l triol 3,20dione 11,21 diacetate) upon treatment with sodium azide in aqueousmethanol according to our process yields over 90% theoretical yield ofthe corresponding 6p-azido-7a-hydroxy-1,2-dihydrodexamethasone11,21-diacetate of good purity in less than 5 days reaction time;whereas treatment of the corresponding l1,8-hydroxy-6a,7a-oxido startingcompound with sodium azide yields less than 2% desired product after 10days reaction time.

By our invention, we have also discovered that by keeping the IIB-loweralkanoyloxy function in the 6B-azido- 7a-hydroxy intermediates and inthe 7u-esters thereof throughout the process, undesirable side reactionsare advantageously minimized in the other steps of the process. Thus,for example, in the process described in the co-pending applications,when dehydroacyloxylating with tetramethylammonium fluoride a6B-azido-7a-lower alkanoyloxy-4-pregnene having a 9a-bromo-115-hydroxygrouping, there is formed, in addition to the desired6-azido-9a-bromo-l1fi-hydroxy-4,6-pregnadiene, a substantial quantity ofa side reaction product, namely, the corresponding 93,11B-oxidoderivative; whereas, when a 6flazido-7aalkanoyloxy-9a-bromo-11fi-alkanoyloxy-4-pregnene is reacted withtetramethylammonium halide according to our improved process, there isobtained a product comprising substantially only6-azido-9wbromo-11p-alkanoyloxy-4,6- pregnadiene.

3 SUMMARY OF THE INVENTION The invention sought to be patented in theprocess aspect of this invention resides in the concept of animprovement in the process of preparing a6-azido-1l5-hydroxy-4,6-pregnadiene-3,20-dione wherein a 6u,7a-oxido-11fl-hydroxy-4-pregnene-3,20-dione starting compound is treated with analkali metal azide in a non-reactive, organic solvent, and either theresulting 6fi-8ZidO-7a,llfldihydroxy-4-pregnene-3,20-dione is treatedwith concentrated hydrochloric acid in a lower alkanoic acid togetherwith an inert solvent, or a 7a-ester of said 6B-azido-7a,1 1B-dihydroxy-4-pregnene-3,20-dione is treated with a dehydroacyloxylatingagent selected from the group consisting of tetraalkylammonium halide inan aprotic solvent, and concentrated hydrochloric acid in a loweralkanoic acid together with an inert solvent, said 7a-ester being amember selected from the group consisting of a 7a-lower alkanoate havingup to 8 carbon atoms and a 7a-hydrocarbonsulfonate having up to 7 carbonatoms, whereby a 6-azido- 1lp-hydroxy-4,6-pregnadiene-3,20-dione isformed;

Said improvement comprising preparing an 11,8-acyloxy derivative of said6u,7a-oxido-11,8-hydroxy-4-pregene-3, 20-dione starting compound priorto treatment with an alkali metal azide, said llp-acyloxy derivativebeing a member selected from the group consisting of 11 fl-formyloxy-,llfi-acetoxyand llfl-halogeno-acetoxy;

And subsequently hydrolyzing said llfi-acyloxy derivative by treating a6-azido-11,8-acyloxy-4-pregnene intermediate selected from the groupconsisting of a 6,6-azido- 7a-hydroxy-11fi-acyloxy-4-pregnene-3,20-dioneand a 6- azido-l113-acyloxy-4,6-pregnadiene-3,20-dione with a hydrolyticagent selected from the group consisting of a basic hydrolytic medium,and, when said 11 8-acyloxy is 115 acetoxy, Flavobacterium dehydrogenans(ATCC 13930).

A preferred species of the improvement process of this invention is thatwherein said llfl-acyloxy is 11,8-ace toxy and said llfl-acetoxy ishydrolyzed by means of Flavobacterium dehydrogenans (ATCC 13930).

The aforementioned preferred specties of our improvement process isparticularly useful when preparing 6- azido-l1fl-hydroxy-4,6-pregnadiene3,20 diones of the corticoid series which have enhancedanti-inflammatory properties, particularly those substituted at C-9 by a9a-bromo-, 9a-chloro-, or preferably, a 9a-fiuoro-, and havingsubstituents at -16 such as 16a-methyl, 16,6- methyl, l6-methylene, 16ahydroxy, and a 16u,l7a-is0- propylidenedioxy function.

The invention sought to be patented in one composition-of-matter aspectof this invention resides in the concept of a chemical compound having amolecular structure comprising a steroid with a 4-pregnene-1lfl-loweralkanoyloxy-3,20-dione nucleus and having an azido group at C-6 and ahydroxyl group or ester thereof at C-7, said ester being an acyl residueof an acid selected from the group consisting of a hydrocarboncarboxylicacid having up to 8 carbon atoms, and a hydrocarbonsulfonic acid havingup to 7 carbon atoms, which compounds are valuable as intermediates inour improved process for preparing 6-azido-4,6-pregnadiene-1lfi-ol-3,20diones described and claimed in co-pending applications Ser. Nos. 58,163and 59,367.

The invention sought to be patented in another composition-of-matteraspect resides in the concept of a chemical compound having a molecularstructure comprising a steroid with a fi-azido-llfl-lower alkanoyloxy-4,6-pregnadiene-3,20-dione nucleus, which are valuable as intermediatesin our improved process for preparing the therapeutically valuable6-azido-1113-hydroxy-4,6-pregnadiene-3,20-diones of the progesterone andcorticoid series and which are also valuable as intermediates inpreparing 6 azido-llfi-lower alkanoyloxy-1,4,6-pregnatriene-3,20- dioneswhich, upon hydrolysis, are convertible to the correspondingtherapeutically active llp-hydroxy compounds.

A preferred species of both composition-of-mattcr aspects describedhereinabove are 6,8-azido-7a-hydroxy-1 lflacetoxy-4-pregnene-3,20-dionesand the 7-acetate esters thereof and6-azido-11B-acetoxy-4,6-pregnadiene-3,20-diones having a cortical sidechain at C-17, particularly those having a 9u-halogeno substituent and asubstituent at C-16 selected from the group consisting of 16e-methyl,16p-methy1, lfi-methylene, l6u-hydroxy and a 16a,17a-isopropylidenedioxyfunction. Of the foregoing, of particular value are those having a9a-fil1010 and a 16-methyl substituent, being intermediates in preparing6-azido corticoids having greatly enhanced activity, namely,6-azido-9a-fluoro-l6a-methyl-4,6-pregnadiene-115,17, 21-triol-3,20-dioneand the 16,3-methyl epimer thereof and their l-dehydroanalogs and the21-lower alkanoate esters (preferably 21-acetate) and 17,21-di-loweralkanoates (e.g. 17,2l-dipropionate) of the foregoing.

General description of the 6-azido-7-oxygenated composition-of-matteraspect of the invention Included among the physical embodiments of the65- azido-7a-oxygenated-4-pregnenes of this invention are 65-azido-h-hydroxy-llfl-lower alkanoyloxy-4-pregnenes and 7-esters thereofof following structural Formula I and the l-dehydro analogs thereof:

CHzZ

Wherein Q is a member selected from the group consisting of hydroxy, ORwherein R is an acyl radical of a hydrocarboncarboxylic acid having upto 12 carbon atoms, and hydrogen provided W is a member selected fromthe group consisting of Hydrogen and (H, lower alkyl);

V is a member selected from the group consisting of hydrogen and an acylradical of an acid selected from the group consisting of ahydrocarboncarboxylic acid having up to 8 carbon atoms andhydrocarbonsulfonic acid having up to 7 carbon atoms;

W is a member selected from the group consisting of hydrogen, (H, loweralkyl), =(H, u-hydroxy) and '(H, a- OR) wherein R is an acyl radical ofa hydrocarboncarboxylic acid having up to 12 carbon atoms, =CHT whereinT is a member selected from the group consisting of hydrogen, loweralkyl, fluorine and chlorine, and when taken together with Q,16a,17a-1ower alkylidenedioxy;

X is a member selected from the group consisting of hydrogen and ahalogen having an atomic weight less than Y is a member selected fromthe group consisting of formyloxy, acetoxy and halogenoacetoxy; and

Z is a member selected from the group consisting of halogen, hydrogen,hydroxy, 0R" wherein R is an acyl radical of an acid selected from thegroup consisting of a hydrocarboncarboxylic acid having up to 12 carbonatoms, and when taken together with Q, l7a,2l-lower alkylidenedioxy.

The alkyl groups included within the definition of substituents W and Tare preferably lower alkyl groups, i.e. hydrocarbon radicals havingpreferably up to four carbon atoms such as methyl, ethyl, n-propyl,iso-propyl, nbutyl, sec.-butyl, and tert.-butyl, although higherhomologs such as pentyl and hexyl come within the scope of thisinvention. a

The alkylidene groups contemplated in the compounds of our invention arepreferably lower alkylidenes, i.e. hydrocarbon radicals havingpreferably up to four carbon atoms and having a terminal double bond,including radicals such as methylene, ethylidene, n-propylidene,isopropylidene, n-butylidene, and sec.-butylidene and the like. The16-lower alkylidene derivatives of this invention (i.e. when W in aboveFormula I is =CHT) are double bonded to the D-ring at C-16. TheIMAM-alkylidenedioxy derivatives have the alkylidene terminal bondsattached to different oxygen atoms, i.e. to the oxygens at C-16 and -17in the case of the 16a,17a-alkylidenedioxy derivatives.

As used in the specification and claims of this application, the termacyl denotes an organic radical derived from an organic acid by theremoval of the hydroxyl group, e.g. acetyl is the acyl radical of aceticacid, benzenesulfonyl is the acyl radical of benzenesulfonic acid, andbenzoyl is the acyl radical of benzoic acid.

The acyl radicals of the compounds of this invention as defined by R, R,and R" in Fonnula I hereinabove include those derived fromhydrocarboncarboxylic acids having up to 12 carbon atoms which may besaturated, unsaturated, straight chain or branched chain, aliphatic,cyclic, cyclic-aliphatic, aromatic, aryl-aliphatic, or alkylaromatic,and may be substituted by hydroxy, alkoxy containing from 1 to 5 carbonatoms or by halogen such as fluorine, chlorine, or bromine. Typicalester groups of the 6-azido-6-dehydroprogesterones of our invention arethus derived from hydrocarboncarboxylic acids such as alkanoic acidsexemplified by formic, acetic, propionic, trimethylacetic, butyric,iso-butyric, valeric, iso -valeric, caproic, caprylic, capric,undecyclic and lauric acids; substituted alkanoic acids such asphenoxyacetic, trifluoroacetic, and fi-chloropropionic acids; aromaticand substi tuted aromatic acids including benzoic, toluic,p-chlorobenzoic acids; arylalkanoic acids such as phenylacetic andphenylpropionic acids; unsaturated acids such as acrylic and sorbicacids; and dibasic acids such as succinic, tartaric and phthalic acids.

The term lower alkanoyloxy is contemplated as including acid radicals oflower alkanoic acids having preferably up to 8 carbon atoms such asradicals obtained from acetic, propionic, butyric, valeric, caprylic,caproic, tert.-butylacetic acid and the like.

The halogens at C-9 as defined by X in above Formula I are bromine,chlorine, and preferably fluorine. The halogens at C-21 as defined by Zin above Formula I are fluorine, chlorine, bromine and iodine, the21-bromoand 21-iodoprogesterones of this invention being valuable mainlyas intermediates.

The acyl radicals contemplated as included within the definition of V inFormula I are those derived from hydrocarboncarboxylic acids having upto 8 carbon atoms including lower alkanoic acids exemplified by formic,acetic, propionic, trimethylacetic, butyric, iso-butyric, tert.-butyric,valeric, iso-valeric, caproic and caprylic; substituted alkanoic acidssuch as trifluoroacetic and B-chloropropionic acids, aromatic andsubstituted aromatic acids such as benzoic, toluic, p-chlorobenzoic, andhydrocarbonsulfonic acids having up to 7 carbon atoms such asmethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid andp-toluenesulfonic acid.

contemplated as included within the halogeno-acetoxy derivatives definedby Y at C-ll are radicals derived from acids such as mono-chloroaceticacid, trichloroacetic acid, bromoacetic acid and, preferably,trifiuoroacetic acid.

The physical embodiments of the 6 3-azido-7a-hydroxyllfi-loweralkanoyloxy-4-pregnene-3,20-diones and 7aesters thereof of Formula I,their method of preparation and use as intermediates in our improvedprocess for preparing 6-azido-11fl-hydroxy 4,6 pregnadiene-3,20- dionesare discussed further hereinbelow in the general description of theprocess aspect of this invention and are described in detail in theexamples, the I-dehydro analogs of Formula I being prepared in similarmanner.

Typical intermediates of Formula I include 6 3-azido-7a-hydroxyprogesterones and their 7a-esters (i.e. compounds of Formula Iwherein Z is hydrogen or halogen) such as,

6/3 azido 70c hydroxy 115,170; bis acetoxy-l6- methyleneprogesterone(i.e. 6,3 azido 70c hydroxy-l6- methylene-4-pregnene-l15,170: diol 3,20dione 11,17- diacetate), the 7-acetate ester thereof, the7-methanesulfonate ester thereof, the 7-p-toluenesu1fonate esterthereof, the 9a-fluoro derivatives of the foregoing, and the l6a-methyland the 16fi-methyl homologs thereof;

6B-azido 7m hydroxy 16 ethylidene-4-pregnene- 11B,l7cc-diOl-3,20-di0l'l11,17-diacetate and the 7ot-acetate ester thereof;

SB-azido 7a hydroxy 9a fluoro -11,6-acetoxy-16a,17a-iso-propylidenedioxy 4 pregnene 3,20 dione and the 7ot-acetate esterthereof; and

GB-azido 7a hydroxy ,21 difiuoro 4 pregnene- 115,170; diol 3,20 dione11,17-diacetate, the 7macetate ester thereof, and the 16a-methyl and themethyl homologs thereof.

Preferred compounds of Formula I are 6/3-azido-7mhydroxy-llfl-loweralkanoyloxy 4 pregnene-3,20-diones of Formula I and 7a-esters thereofwhich have a cortical side chain at C-l7 (i.e. compounds of Formula Iwherein Z is hydroxy or acyloxy), and particularly those having ahalogen at C-9, e.g. a 9a-bromo-, 9a-chloro-, or preferably a9oc-fll1010. Particularly valuable are the 6B-azido- 7a-hydroxy 9ozfluoro 11B lower alkanoyloxy-4-pregnene-3,20-diones of Formula I havinga substituent at C-16 such as a 16-methylene, 16u-hydroxy or derivativethereof or, preferably, a 16u-methyl or 16/3-methyl group. Includedamong the preferred intermediates of Formula I are compounds such as,

6,8 azido 7a hydroxy 4 pregnene 1lB,l6oz,17 x, 21-tetrol-3,20-dione11,16,21-triacetate, the 7a-acetate ester thereof, and the 9a-fiuoroderivatives of the foregoing;

6B-azido 7a hydoxy 16 methylene 4 pregnene- 11,8,17u,21-triol-3,20-dione11,21-diacetate, the 7-acetate ester thereof, and the 9a-fiuoroderivatives of the foregoing; and

6p azido 7oz hydroxy 16oz methyl 4 pregnene- 11,6,l7a,21-triol 3,20dione 11,21 diacetate, and the 16B-methyl epimer thereof and their7a-acetate esters and the 9a-bromo-, 9a-chloroand 9a-fluoro derivativesof the foregoing.

General description of the 6-azido-11l3-loweralkanoyloxy-4,6-pregnadiene composition-of-matter aspect of theinvention Included among the physical embodiments of the 6-azido-llfi-lower alkanoyloxy-4,6-pregnadiene-3,20-diones of thisinvention are members selected from the group consisting of compounds offollowing structural Formula II and the l-dehydro analogs thereof:

wherein Q, W, X and Y are as defined hereinabovefor Formula I andwherein Z is a member selected from the group consisting of hydrogen,halogen, hydroxy, OR" wherein R" is an acyl radical of an acid selectedfrom the group consisting of a hydrocarbonsulfonic acid having up to 7carbon atoms and a hydrocarboncarboxylic acid having up to 12 carbonatoms, and when taken together with Q, 17a,21-10WI alkylidenedioxy.

The 66 azido-11,8-lower alkanoyloxy-4,6-pregnadienes of Formula II areintermediates in the process of this invention and are immediateprecursors of the pharmacologically active llB-hydroxy derivatives whichare described and claimed in co-pending applications Ser. Nos. 58,163and 59,367 of common assignee as the instant application. The6fi-azido-11fl-lower alkanoyloxy-4,6-pregnadienes of Formula II are alsoconvertible to the corresponding l-dehydro analogs of Formula II (forexample, by reaction with diehlorodicyanobenzoquinone in a nonreactive,organic solvent in the presence of a strong acid) and the resulting6-azido-l1B-lower alkanoyloXy-1,4,6 pregnatrienes upon hydrolysis yieldthe pharmacologically active corresponding 11fl-hydroxy-1,4,6-pregnatrienes.

The physical embodiments of the 6-azido-11B-lower alkanoyloxy 4,6pregnadiene 3,20 diones of this aspect of our invention and their use asintermediates in our improved process are discussed further hereinbelowin the general description of the process aspect of this invention andare described in detail in the examples, the l-dehydro analogs ofFormula II being prepared in similar manner.

Typical intermediates of Formula II include 6-azido- 11 fl-loweralkanoyloxy-6-dehydroprogesterones and derivatives thereof (i.e.compounds of Formula II wherein Z is hydrogen or halogen) such as,

6 azido 115,170; diacetoxy 16 methylene-6-de hydroprogesterone (i.e.6azido 16 methylene-4,6- pregnadiene-llB,17a-diol-3,20-dione11,17-diacetate), the 9a-fluor0 derivatives thereof, and the 16a-methyland 165- methyl homologs of the foregoing;

6 azido 16 ethylidene 4,6 pregnadiene-1lfl,l7adiol-3,20-dione 11,17-diacetate;

6 azido9a-fiuoro-11/3-acetoxy-16a,17a-iso-propylidenedioxy-4,6-pregnadiene-3,ZO-dione;and

6 azido 911,21-difluoro-4,6-pregnadiene-115,17a-dil- 3,20-dionell-acetate and the l6a-methyl and 16 8-methyl homologs thereof.

Preferred compounds of Formula II are those having a cortical side chainat C-17 (compounds of Formula I wherein Z is hydroxy or acyloxy), andparticularly those having a halogen at C 9, preferably a 9a-fluoro.Particularly valuable intermediates are the 6-azido-9a-fiuoro-l 1 3-lower alkanoyloxy-4,6-pregnadiene-3,20-diones of Formula II having asubstituent at C-16 selected from the group consisting of l6-methylene,16a-hydroxy or derivatives thereof and, preferably a 16a-methy1 or l63-methyl group. Included among the preferred intermediates of Formula IIare compounds such as,

6 azido 4,6-pregnadiene-ll;3,17a,21-triol-3,20-dione 11,21-diacetate andthe 9oz-fil10l0 derivatives thereof;

6 azido 4,6-pregnadiene-11,8,16a,17a,21-tetrol-3,20- dione11,16,21-triacetate and the 9a-fiuoro derivatives of the foregoing;

6 azido 16 methylene-4,6-pregnadiene-11/3,l7a,21- triol-3,20-dione11,21-diacetate and the 9a-fluoro derivatives of the foregoing; and

6 azido 16a-methyl-4,G-pregnadiene-11,8,17a,21-triol- 3,20-dione11,21-diacetate and the 16 8-methyl epimer thereof and their 7a-acetateesters and the 9a-bromo-, 9achloro-, and the 9oc-flll0f0 derivatives ofthe foregoing.

GENERAL DESCRIPTION OF THE PROCESS ASPECT OF THE INVENTION In co-pendingapplications of common assignee as the instant application, U.S. Ser.Nos. 58,163 and 59,367 filed July 24, 1970 and July 29, 1970,respectively, are described pharmacologically active6-azido-4,6-pregnadienes including 11fl-hydroxy-G-azido-4,6-pregnadienesdefined by structural Formula III in Chart A hereinbelow, and thel-dehydro analogs thereof wherein Q, W, X, and Z are as hcreinabovedefined for Formula I.

The compounds of Formula III wherein Z is hydrogen are described asprogestational agents and as possessing anti-androgenic activity, thusbeing useful in the treatment of disorders such as acne or benignprostatic hypertrophy; those compounds wherein Z is fluoro and Q ishydroxy are described as having topical anti-inflammatory activity; andthose compounds wherein Z is hydroxy or hydrocarboncarboxyloxy aredescribed as possessing glucocorticoid activity and, when Q is hydroxyor an ester thereof, as being particularly valuable as anti-inflammatoryagents. The compounds of Formula III are further described as having anactivity similar to, but enhanced over, that of the corresponding6-unsubstituted-6,7-dehydro prior art analogs. Thus, particularlypreferred 6-azido-11B-hydroxy- 4,6-pregnadiene corticoids of Formula IIIare 6-azido-1,2- dihydro 6,7-dehydro analogs of6-unsubstituted-11fl-hydroxy-1,4-bis-dehydro-corticoids known to possessuseful glucocorticoid and corticosteroid properties, e.g.9u-fluorollfl-hydroxy-corticoids such as dexamethasone (i.e. 9afluorol6a-methyl-1,4-pregnadiene-11/3,17a,21-triol-3,20- dione), betamethasone(9a-fiuoro-16fl-methyl-1,4-pregnadiene-l1 8,17a,21-triol-3,20-dione),triamcinolone (i.e. 9afluoro 1,4-pregnadiene-11/3,16a,17a,21-tetrol-3,20-dione) and prednylidene (i.e.16-methylene-1,4-pregnadiene-l1,3, l7ot,21-triol-3,20-dione) and the2l-diethylaminoacetate ester thereof.

Co-pending application Ser. Nos. 58,163 and 59,367 describe processeswhereby the therapeutically valuable 6-azido-4,6-pregnadienes of FormulaIII are conveniently prepared from the corresponding6a,7ot-oxido-4-pregnenes, which processes are shown diagramaticallyhereinbelow in Chart A, substituents Q, W, X and Z in structuralFormulae A, B, C, and III being as defined hereinabove for Formula I:

a cone. HCl in l organic solvent 1 TETRAALKYL- f AMMONIUM HALIDE O acyl2. cone. HCl in 0 organic solvent CHART A ture in which water is present(e.g. aqueous methanol, aqueous dioxane, aqueous dimethylformamide,aqueous methanol/dioxane, aqueous tetrahydrofuran, and the like) undermild conditions in neutral or slightly acidic or basic media whereby theepoxy function is split and there is introduced into the molecule a6B-azido-7a-hydroxy system to form an intermediate, i.e. a6,8azido-7a,ll;3-dihydroxy-4-pregnene of Formula B (e.g.6fi-azido-7a,ll;8-dihydroxy l6 methylene l7u-acetoxy-4-pregnene-3,20-dione and 6fi-azido-4-pregnene-7a,l l}8,17a,21-t6'[IOl-3,20- dioneZl-acetate, respectively).

When carrying out the two-step prior art process (i.e. A B IH), the6B-azido-7u,1lfl-dihydroxy intermediate, B, is then dehydrated at C-7(6) by treatment with concentrated hydrochloric acid in a lower alkanoicacid (e.g. acetic acid) together with an inert solvent (e.g. dioxane) toproduce a pharmaceutically active 6 azido-llp-hydroxy-4,6-pregnadiene ofFormula III.

Preferably, when carrying out the three-step prior art process (i.e. A-.B- C III), the 7u-hydroxy function in the thereby formed intermediateof Formula B is esterified utilizing known esterification procedures (e.g. that utilizing acetic anhydride in pyridine at room temperature). Treatment of the resulting 6B-azido-7a-acyloxy-1lfi-hydroxy- 9tx-X-l6-W-17u-Q-2l-Z-4-pregnene-3,ZO-dione (Formula C) intermediate (e.g.6,8-azido-7a,17a-diacetoxy-1lB-hydroxy-16-methylene-4-pregnene-3,20-dioneor 6B-azido-4- pregnene-7a,l1B-17a-2l-tetrol-3,20-dione 7,21 diacetate,respectively) with a tetraalkylammonium halide (e.g. tetramethylammoniumfluoride) in an aprotic solvent, preferably acetonitrile ordimethylformamide, yields a pharmacologically active 6azido-11p3-hydroxy-9a-X-16- W-17a-Q-2l-Z-4,6-pregnadiene-3,20 dione ofcompound III, e.g. 6 azido-11/3-hydroxy-16-methylene 17ozacetoxy-4,6-pregnadiene-3,20 dione and 6-azido-6-dehydrohydrocortisone21-acetate (i.e. 6-azido-4,6-pregnadiene- 115,170: 21 triol-3,20-dione21-acetate), respectively. Alternatively, the dehydroacyloxylation step(C III) may be carried out utilizing concentrated hydrochloric acid inacetone or preferably in a solvent mixture comprising a lower alkanoicacid (e.g. acetic acid) and dioxane.

The necessary 6a,7a-oxido-4-pregnene-3,20-dione starting compounds (A)for the prior art process are conveniently prepared according to knownprocedures from the corresponding6,7-unsubstituted-4,6-pregnadiene-3,20- dione such as by reaction with aperacid in a non-reactive, organic solvent, e.g. with reagent-solventcombinations such as meta-chloroperbenzoic acid in solvents such asacetone or ethyl acetate, meta-chloroperbenzoic acid in methylenechloride/tert.-butanol, or with mono-perphthal ic acid in solvents suchas chloroform or methylene chloride. In turn, the6,7-unsubstituted-4,6-pregnadiene3,20- dione precursors are convenientlyderived from the corresponding 6,7-dihydro analogs by procedures knownto effect dehydrogenation between C-6 and C7, such as those utilizingchloranil or 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ). When thestarting steroid has a l6-alkyl substituent, e.g. l6B-methyl 4pregnene-3,20-dione, in order to minimize the possibility ofrearrangement reactions, introduction of the 6-dehydro bond ispreferentially effected by the use of2,3-dichloro-5,6-dicyanobenzoquinone in the presence of acid (e.g. DDQin dioxane and hydrogen chloride gas).

When preparing the 6-azido-4,6-bis-dehydropregnanes of Formula III inthe manner outlined in Chart A, it is usually preferable to have presentin the starting 611,70- epoxypregnene (A) all the substituents desiredin the final 6-azido-4,6-pregnadiene product, III.

When carrying out the first step (i.e. A B) of the prior art process,the opening of the 6u,7a-oxido function to form the corresponding613-azido-7a-hydroxy intermediate B is usually completed in a relativelyshort time when the ll-carbon is unsubstituted or has an ll-ketosubstituent. Thus, for example, 6a,7a-oxidol 6-methylene- 1017a-acetoxy-4-pregnene-3,2t0-dione (an ll-unsubstituted analog of a6a,7a-oxido progesterone of Formula A, Chart A) upon treatment withsodium azide in aqueous methanol in the presence of acetic acid at roomtemperature for about 18 hours yields about to theoretical yield of6fl-azido-7ot-hydroxy-16-methylene-17aacetoxy-4-pregnene-3,20-dione.Similarly, reaction of 6a, 7oc-OXid0 4pregnene-l7u,21-diol-3,11,20-t1'i0ne 21-acetate (an ll-keto analog of a6a,7o-oxido-4-pregnene of Formula A, Chart A, having a cortical sidechain at C-l7) with sodium azide in aqueous methanol in the presence ofacetic acid at room temperature yields, after about 18 hours reactiontime, over 90% theoretical yield of purified 65 azido7a-hydroxy-4-pregnene-17a,21-diol-3,11, 20-trione Zl-acetate.Furthermore, when the foregoing reaction on the ll-keto compound iscarried out at about 50 C., the reaction is essentially completed inless than an hour.

We have found, however, that when an l1B-hydroxyl group is present inthe 6a,7a-oxido-4-pregnene-3,20-dione starting compound, A, conversionof the 60,7oc-0Xid0 function to a Gfi-EIZldO-7oc-hYdI'OXY derivativeproceeds very slowly, providing an opportunity for competing sidereactions to occur and resulting in poorer yields of 6B- azido-701,11fl-dihydroxy-4-pregnene 3,20 dioues of less purity than those obtainedwhen an ll-unsubstituted or an 1l-keto-6a,7a-oxido-4-pregnene is reactedwith an alkali metal azide. Thus, for example, when thellfl-hydroxylated compound, 6a,7u-oxidohydrocortisone 21-acetate (i.e.60:,70; oxido-4-pregnene-11/3,17a,21-triol-3,20-dione 21-acetate) isreacted with sodium azide in aqueous methanol at room temperature (asdescribed in Example 5) in a manner similar to that in which theabove-mentioned :6a,7a-oxido-1l-unsubstituted and 6a,7oc-0XidO-l1-keto-4-pregnenes were treated, only one third of the starting compoundhad reacted after 18 hours and after 4 days, when thin layerchromatographic analysis indicated no further starting60:,70c-0XidO-4-P1'6gt16116 remained in the reaction mixture, there wasisolated 68% theoretical yield of 6B-azido-7a-hydroxyhydrocortisone2l-acetate (i.e. 618 azido 4 pregnene-MA1/3,17a,21-tetrol-3,20- dione2l-acetate).

We have discovered further that, when the 6u,7a-oxido- 11B hydroxy 4pregnene intermediate also has a 90!.- halogeno group (such as in600,704 0Xld0-9u flllO1O-16amethyl-4-pregnene-11B,17x,2l-triol-3,20-dione 21-acetate) fission of the 6a,7a-oxido group withsodium azide under the conditions of the prior art process (as describedin Example 2) proceeds at an even slower rate with the result that after10 days reaction time, when thin layer chromatographic analysisindicates substantially all the 60:,7u-0XidO-9a-flll010 11,8hydroxy-4-pregnent starting compound has been consumed, only about 2% ofthe desired 618 azido 70c hydroxy 9a fiuoro-16a-methyl-4-pregnene-3,20-dione 2l-acetate is isolated from the reaction mixture.Moreover, isolation is accomplished with difliculty due to the presenceofdecomposition products and products of side reaction. Similarly, whenthe 1-6;?- methyl epimer of the foregoing 6a,7aoxido-4-pregnene isreacted with sodium azide under the conditions of the prior art process,after the 15 days reaction time required to consume substantially allthe 6a,7a-oxido-4-pregnene starting compound, there is isolated lessthan 2% theoretical yield of the desired6fl-azido-7a-hydroxy-9a-fluorol6/3-methyl 4pregnene-l15,17a-21-triol-3,20-dione 21- acetate intermediate B.

By our invention, we have discovered that, when the hydroxyl group in a6oz,7ot oxido 90c halogenollfi-hydroxy 4 pregnene A (e.g.60:,7oz-OXidO-9a-fill0f0- 16a-methyl 4pregnene-11;3,l7a,2l-triol-3,20-dione 2lacetate) is converted to anll-lower alkanoate ester (preferably ll-acetate) prior to reaction withsodium azide, the opening of the 60,7u-0Xid0 ring occurs at a fasterrate and there is obtained good yields of 6fl-aZido-7ahydroxy 11B loweralkanoyloxy-4-pregnene intermediate of good purity which is easilyisolated from the reaction mixture. Thus, for example, when60:,7ot-OXidO-9otfluoro-l6a-methyl 4 pregnene-Il/3,17a,2l-triol-3,20-dione 11,21-diacetate is treated with sodium azide accord ing to ourimproved process, in less than days there is obtained over 90%theoretical yield of 6fi-azido-7a-hydroxy-9u-fiuoro 16a methyl 4pregnene-116,17 11,21- tri0l-3,20-dione 11,21-diacetate. Thus, by ourimproved process, in less than /2 the reaction time required in theprior art process, there is produced over a forty-fold increase inproduct yield (i.e. from about 2% to about 91% theoretical yield).Similarly, when the 16B-methyl epimer of the foregoing is reactedaccording to our improved process, in 7 days reaction time there isobtained 95.4% theoretical yield of purified 6B-azido 7oz hydroxy-165-methyl-4-pregnene-l1,8,17a,21 triol-3,20-dione 11,21-diacetate, at leasta 40-fold yield increase of product in less than half the reaction timerequired by the prior art process.

When our improvement process is carried out on a 9- unsubstituted 11,9hydroxy-6a,7a-oxido 4 pregnene, improved yields of product are likewiseobtained in a shorter time than by the prior art method. Thus, when6a,7a-oxidohydrocortisone 11,21-diacetate is reacted according to ourprocess with sodium azide under conditions similar to those under which6a,7ot-hydrocortisone 2l-acetate is treated, 30% conversion of thestarting 60:,- 7a-oxido 11B acetoxy 4 pregnene occurs in three hours (asopposed to 18 hours for 30% conversion in the prior art process) andafter 18 hours, there is isolated from the reaction mixture 90%theoretical yield of 6,3- azido 7oz hydroxyhydrocortisone11,21-diacetate of good purity which is a 22 percent yield increase inabout one sixth the reaction time required in the prior art process forthe conversion of 60:,7oc-OXidOhYdlOCOltiSOI16 21- acetate, A, to a 68%theoretical yield of the corresponding 6 8-azido 7ahydroxyhydrocortisone 2l-acetate, B.

Our invention finds its greatest use when preparing 6- azido-9a-fluoro11B hydroxy-4,6-pregnadienes, a preferred species being that utilizing6u,7a oxido-l lfi-lower alkanoyloxy-4-pregnene 3,20 dione startingcompounds having a 9a-fluoro substituent and a corticoid side chain atC-17, preferably also having a substituent at C-16 selected from thegroup consisting of methylene, a-hydroxy, ii-methyl and a-methyl since,by utilizing these starting compounds, our process produces in goodyields, 6-azido 11B lower alkanoyloxy-4,6-pregnadiene intermediates ofFormula II, which, upon hydrolysis, yields 6-azido 11,8hydroxy-4,6-pregnadienes of Formula III having potent anti-inflammatoryactivity.

In brief, our improved process comprises esterifying the llfl-hydroxygroup in a 60,70c-0Xid0 11B hydroxy-4- pregnene-3,20-dione (compound A)prior to carrying out the process outlined in Chart A and thenpreferably bydrolyzing the 11-acetate after formation of novelintermediates of Formula II which are ll-lower alkanoate esters ofcompounds of Formula III in Chart A.

Our improved process is preferably carried out on the ll-acetate estersince it is easily prepared and remains unchanged throughout thereaction sequence outlined in Chart A, and is easily hydrolyzed in goodyields either chemically via mild alkaline hydrolysis or, preferably, ishydrolyzed by means of the organism F lavobacterium dehydrogenans var.Hydrolyticum (ATCC 13930) utilizing standard procedures.

Our process is also conveniently carried out utilizing the ll-formateesters of ll-halogenoacetate esters, preferably the ll-trifluoroacetate,all of which are prepared with relative ease and can be hydrolyzed undermild alkaline hydrolytic conditions. Contemplated as included within theterm ll-halogenoacetate esters are esters derived from bromoacetic acid,chloroacetic acid, trichloroacetic acid and, preferably, trifiuoroaceticacid.

The preferred ll-acetate esters of compounds defined by Formula A, ChartA, are prepared from the corresponding llfi-hydroxy 6a,7aoxido-4-pregnene under mild basic conditions known to esterify secondaryhydroxyls such as that utilizing a large molar excess of aceticanhydride in pyridine. When carrying out the prior art process outlinedin Chart A, it is desirable that the hydroxyl group at (3-21 beprotected such as by an ester group; accordingly, if desired,esterification at C-21 can be carried out concomitantly withesterification at C-ll. When preparing an ll-acetate ester by means ofacetic anhydride in pyridine alone at room temperature, theesterification proceeds slowly requiring several weeks for completion;however, when carried out at about 50 C., good yields of the ll-acetateester are obtained after three days reaction time. A preferred method ofpreparing the ll-acetate ester is to add 4-dimethylaminopyridine to theaforedescribed esterification medium and there are obtained excellentyields of ll-acetate ester in less reaction time. Thus, esterificationof6a,7u-oxido-9a-fluoro-16amethyl-4-pregnene-l1/3,17a,21-triol-3,20-dione21 acetate with acetic anhydride in pyridine in the presence of 4-dimethylaminopyridine as described in Preparation 1-C producesapproximately theoretical yields of the corresponding ll-acetate esterin 18 hours. Gene-rally, when preparing an ll-acetate ester of anll-hydroxysteroid defined by Formula A, Chart A, to one gram ofllB-hydroxy- 6a,7u-oxido 4 pregnene dissolved in 10 ml. of pyridinethere is added 2 ml. acetic anhydride and 50 mg. of 4-dimethylaminopyridine. The reaction is preferably carried out at roomtemperature from 10 to 20 hours. Esterification of an1l-hydroxy-4-pregnene of Formula A, Chart A, can also be carried outwith acetic anhydride and 4-dimethylaminopyridine alone, or with4-dimethylaminopyridine mixed with triethylamine. When carrying out ourprocess utilizing the ll-acetate esters of the llfl-hydroxyintermediates A, Chart A, which also have a 17a-acyloxy and/ or a2l-acyloxy group, the esters at C-17 and/or at 0-21 in the starting6a,7ot-OXid0 11B acetoxy-4-pregnene-3,20-dione may be derived from anyhydrocarboncarboxylic acid having up to 12 carbon atoms and there willbe obtained the corresponding 6,8-azido-7a-hydroxy- 11 fl-acetoxy-lhand/or 21 acyloxy 4 pregnene-3,20- dione, convertible to a 7u-ester followedby dehydroacyloxylation, and there will be obtained the corresponding6-azido 11B acetoxy-17uand/or 2l-acyloxy4,6-pregnadiene-3,20-dione(Formula III, Chart A).

In the preferred mode of our improved process, the ll-acetate ester of6a,7a-oxido-ll 8-hydroxy-4-pregnenes of Formula A, Chart A, is carriedthrough the sequence of three steps A- B C III or through two steps A BIII as outlined in Chart A (and as discussed hereinabove and asillustrated in detail in the examples) and there is obtained thecorresponding ll-acetate ester of the6-azido-11B-hydroxy-4,G-pregnadiene of Formula II. The manner ofcarrying out the reaction steps and steps A B III is essentially thesame as that de scribed for the prior art process in co-pendingapplications Ser. Nos. 58,163 and 59,367.

When carrying out the preferred mode of our improved process utilizingan ll-acetate ester intermediate A, after preparation of the6,8-azido-7a-hydroxy-11,8-hydroxy-4- pregnene intermediate B, the7a-hydroxy function is preferentially converted to the 7-acetate esterand the resulting 6fi-azido-7a,llfi-diacetoxy 4 pregnene isdehydroacetoxylated by means of a tetramethylammonium halide, preferablyteramethylammoniumfiuoride. We have found that the acetylation of the7ot-hydroxyl group is advantageously carried out in the presence of4-dimethylaminopyridine under conditions similar to those describedhereinabove for the esterification at C-11. When 4-dimethylaminopyridineis used in this esterification step, the reaction proceeds at a fasterrate giving rise to greater yields 13 'of purer product than whenesterification is carried out utilizing pyridine and acetic anhydridealone.

When preparing a 6-azido-9a-bromo-11,8-hydroxy-4,6- pregnadiene from a6a,7a-oxido-9a-bromo-1lfl-hydroxy- 4-pregnene by the process describedin co-pending applications Ser. Nos. 58,163 and 59,367 of commonassignee, in the last step of said process a 6B-azido-7a-acyloxy-9wbromo-l1B-hydroxy-4-pregnene upon treatment with tetraalkylammoniumhalide in acetonitrile (for example) yields a product mixture comprising6-azido-9t3,11B-oxido-4,6-pregnadiene together with6-aZld0-9oc-b10ll10-11B- hydroxy-4,6-pregnadiene.

When preparing a 6-azido-9a-bromo-1LB-hydroxy-4,6- pregnadiene by ourimprovement process, the presence of the ll-acetate functionadvantageously eliminates the formation of the 95,115-oxido side productand there is produced a product comprising mainly the desired6;S-azido-9abromo-11fl-acetoxy-4,6-pregnadiene.

After carrying out the reaction sequences outlined in Chart Ahereinabove utilizing preferentially an ll-acetate ester of thell-hydroxy compounds shown therein, there is obtained an ll-acetateester of compound HI. Hydolysis of the ll-acetate is easily effectedutilizing chemical means, e.g. mild alkaline hydrolytic methods or,preferably, microbiologically utilizing F lavobacterium dehydrogenans(ATCC 13930) according to procedures known in the art.

By mild alkaline hydrolytic means is contemplated reaction mediacontaining a hydroxyl ion (such assupplied by alkali metal carbonates orhydroxides) in an aqueous media, e.g. in aqueous methanol: or mediacontaining an alkoxide ion (such as supplied by alkali metal alkoxide)in anhydrous alkanols, e.g. anhydrous methanol.

When hydrolyzing the ll-acetate ester by means of Flavobacleriumdehydrogenans (ATCC 13930), all other acetate groups present in themolecule will also be hydrolyzed; similarly, when hydrolyzing under mildalkaline hydrolytic media, all other primary and escondary hydroxylgroups will be hydrolyzed and, depending on the hydrolytic conditions,some tertiary esters may be hydrolyzed.

In turn, any hydroxy group present in a6-azido-l1fihydroxy-4,6-pregnadiene thus prepared may be esterifiedutilizing neutral or basic acylating reagents according to prceduresknown in the art.

When utilizing an ll-formate ester in our improvement process, thell-formate esters are conveniently prepared by known proceduresutilizing formic acid in the presence of p-toluenesulfonic acid. Underthese conditions, all primary, secondary and tertiary hydroxyl groups inthe 6a,7a-oxido-4-pregnene will also be esterified and will remainunchanged throughout the process but, when desired, can be easilyhydrolyzed at room temperature by means of dilute sodium hydroxide inmethanol. The 11- formate ester is preferably introduced in the moleculeprior to the 60:,7oc-OXld0 group since under the condition necessary toprepare the ll-formate ester, fission of the 6u,7ot-oxido will occurwith formation of undesirable side products. Thus, for example,9ot-flUOIO-16a-IY16thYl- 4,6-pregnadiene-11fi, 17a,21-triol-3,20-dione21-acetate upon treatment with formic acid in the presence of catalyticquantities of p-toluenesulfonic acid yields the corresponding11,17-diformate which, upon treatment with monoperphthalic acid inmethylene chloride produces the requisite 6a,7a-oxido-1lfi-formyloxystarting compound for our process, i.e.6u,7a-oxido-9a-fiuoro-16a-methyl-4- pregnene-l1a,17a,21-triol-3,20-dione11,17-diformate 21- acetate. Reaction of the foregoing with sodium azideyields 6B-azido-7a-hydroxy 9a fiuoro-16a-methyl-4-pregnene-l15,17a,2l-triol-3,20-dione 11,17-diformate 21- acetate.Treatment thereof with acetic anhydride in pyridine (preferably in thepresence of 4-dimethylaminopyridine) yields the corresponding 7u-acetateester which upon reaction with tetramethylammonium fluoride inacetonitrlle or with concentrated hydrochloric acid in aqueous dioxanewill yield 6-azido-9a-fiuoro-16a-methyl-4,6-pregnadiene-11B,17a,21-triol-3,20-dione 11,17 diformate 21-acetate.Hydrolysis therdeof with dilute aqueous sodium hydroxide in methanol atroom temperature yields 6-azido 9afluoro-l6tat-methyl-4,6-pregnadiene-115,17a, 21 triol 3,20-dione havingenhanced anti-inflammatory activity.

ll-halogenoacetate ester starting compounds of our process areconveniently prepared from the corresponding llfl-hydroxy compounds bytreatment with the corresponding acid anhydride in pyridine. Thus, forexample, 6a,7u-oxido-9o-fluoro 16a methyl-4-pregnene-115,17021-triol-3,20-dione 21-acetate, when treated with chloroacetic anhydrideor trichloroacetic anhydride in pyridine at room temperature accordingto known procedure is converted to the corresponding ll-ester, e.g. the11- chloroacetate and ll-trichloroacetate, respectively. Theaforementioned ll-chloroacetate esters remain unchanged throughout thetransformations outlined in Chart A, and after preparation of6-azido-1l-haloalkanoyloxy-4,6-pregnadiene, e.g. the ll-chloroacetateand the 11-trichloroacetate, respectively, of6-azido-9u-fiuoro-16a-methyl-4,6- pregnadiene-11B,17a,21 triol3,20-dione ZI-acetate, the ll-halogenoacetate ester is convenientlyhydrolyzed with dilute aqueous sodium hydroxide in methanol togetherwith any 21-ester which may be present.

The halogenoacetate ester preferred for use in our process is thell-trifiuoroacetate ester which is conveniently prepared from thecorresponding 11tl-hydroxy-4- pregnene of Formula A, Chart A, byreaction with one molar equivalent of trifiuoroacetic anhydride inpyridine at 10 C.

When carrying out our improvement process utilizing anll-trifiuoroacetate ester of a 60:, 7a-oxido compound of Formula A,Chart A, as starting compound, it is necessary that the step of opening-6a,7a-oxido function utilizing sodium azide in aqueous methanol becarried out in neutral or slightly acidic media since, even underslightly alkaline conditions, the ll-trifiuoroacetic acid ester willhydrolyze with the resulting disadvantage of the prior art processdiscussed hereinabove. The reaction mixture of the 6a,7a-oxido steroidand sodium azide in aqueous methanol is kept slightly acid by theaddition of small quantities of acetic acid.

'When utilizing an ll-trifluoroacetate ester of anhydroxy-4-pregnene-3,ZO-dione in our process, after conversion of a6a,7a-oxido1lfi-trifiuoroacetoxy-4-pregnene- 17e,21-diol-3,20-dioneZI-acetate to the corresponding 6fl-azido-7u-hydroxy derivative asdiscussed hereinabove, the 7a-hydroxy is preferentially converted to the7a-acetate ester. By varying the conditions of the acetylation, one canobtain either an 11li-hydroxy-6fi-azido-7a-acetoxy derivative or a6B-azido-7a-1lfl-diacetate derivative. For example, treatment of6,8-azido 7a hydroxy-9u-fluoro- 11B trifluoroacetoxy 16amethyl-4-pregnene-17a,21- diol-3,20-dione 21-acetate with an equimolarquantity of acetic anhydride in pyridine will yield the corresponding6fl-azido 70c acetoxy-llB-hydroxy intermediate which, upon treatmentWtih tetramethylammonium fluoride will yield the pharmacologicallyactive llfi-hydroxy steroid, e.g. 6 azido 9a fluoro 16ccmethyl-4,6-pregnadiene- 11,6,17a,21-triol-3,20-dione 2l-acetate. By thismethod there is thus advantageously eliminated the additional step ofhydrolyzing the ll-ester.

Alternatively, when a molar excess of acetic anhydride is employed, and4-dimethylaminopyridine is used alone or together with pyridine, the6fi-azido-7a-hydroxy-llfltri'fluoroacetoxy-4-pregnene intermediate isconverted to the corresponding 7,11-diacetate, which, upondeacetoxylation according to our process will yield a6-azido-11flacetoxy-4,6-pregnadiene of Formula I, e.g.6-azido-9atluoro-llB-acetoxy 16oz methyl-4,6-pregnadiene-17a,21- diol3,20 dione 21-acetate. Hydrolysis thereof either chemically ormicrobiologically will then yield the corresponding 11,21-diol ofFormula III, Chart A, having 15 anti-inflammatory activity, e.g.6-azido-9'u-fiu0ro-16amethyl-4,6-pregnadiene-l1,8,17a,21-triol-3,20-dione.

In our improved process, the 6-azido-11/8-a1kanoyloxy-4,6-pregnadiene-3,20-dione having a cortical side chain at C-21 isconvertible to the corresponding C-21-unsubstituted-llfl-loweralkanoyloxy progesterone compound or to a therapeutically active21-bromo-, 21-chloroor 21- fiuoro derivative thereof utilizing knownmethods. Thus, 6azido-9rx-fiuoro-6-dehydro-hydrocortisone-11,2l-diacetate upon selectivehydrolysis with potassium bicarbonate in aqueous methanol yields thecorresponding ll-acetate- 21-01 which upon treatment withmethanesulfonyl chloride in pyridine produces the correspondingll-acetate 21 methanesulfonate. Treatment of the foregoing with sodiumiodide in acetone followed by reduction of the thereby formedll-acetate-Zl-iodo derivatives yields the correspondingllfi-acetoxyprogesterone derivative, e.g. 6- azido- 9a-fluoro-11/3-acetoxy 4,6 pregnadiene-Ho ol- 3,20-dione. Hydrolysisthereof by means of Flavobacterium dehydrogenans yields6-azido-9a-fiuoro-4,6-pregnadiene-l 1,8,17u-dil-3 ,20-dione:

Alternatively, the -11;3-acetoxy-21-iodo derivatives are convertible toother pharmacologically active 21-halogene-4,6-pregnadienes. Forexample, '6-azido-9a-fiuoro- 21-iodo-11p-acetoxy 4,6pregnadiene-17a,ol-3,20-dione upon treatment with silver fluoride inmoist acetonitrile will yield the corresponding 21-fiuoro derivativewhich upon hydrolysis of the ll-acetate ester yields 6-azido-901,2l-difluoro-4,6-pregnadiene-11fi,17a-diol having topicalanti-inflammatory activity.

The following examples are illustrative of the procedure employed incarrying out the process of this invention but are not to be construedas limiting the scope thereof, the scope of the invention being definedonly by the appended claims.

PREPARATION 1 6a,7a-oxido-9a-fluorol'6-methyl-4-pregnene-1 1/3,17a,21-triol-3,20-dione 11,21-diacetate (A)9a-fiuoro-16-methyl-4,6-pregnadiene-1 1,8,17a,21- triol-3,20-dione21-acetate (1) Add 10.2 g. of dichlorodicyanobenzoquinone to 12 g. of9a-fiuoro- 16a--methyl-4-pregnene-11,3,17a,21- triol-3,20-dione21-acetate in 600 ml. of dioxane, then bubble in anhydrous hydrogenchloride with stirring for minutes. Continue stirring at ambienttemperature for 2.5 hours. Filter the reaction mixture and evaporate invacuo to a residue comprising 9a-fiuoro-16a-methyl-4,6-pregnadiene-11,8,17a,21-triol-3,20-dione 21-acetate. Purify bydissolving the residue in ethyl acetate, wash the ethyl acetate solutionwith dilute sodium hydroxide, then with water. Dry the organic solutionover magnesium sulphate, filter, then evaporate in vacuo to a residue.Crystallize the residue from acetone-hexane to give 9a-fiuoro-16u-methyl-4,6-pregnadiene 11 3,17oc,21 triol-3,20-dione 21-acetate.

(2) In similar manner, treat 9'a-fluoro-16B-methyl-4- pregnene11p,l7a,21 triol 3,20 dione 21-acetate with dichlorodicyanobenzoquinoneand anhydrous hydrogen chloride in dioxane at room temperature. Isolateand purify the resultant product in the manner described to obtain 9ozfluoro-16/8-methyl-4,6-pregnadiene-11fi,17u,21- triol-3,20-dione21-acetate.

(B) 6a,7a-oxido-9m-fluoro-16-methyl-4-pregnene-11B,l7a,21-triol-3,20-di0ne 21-acetate (1) To 13 g. of9a-fluoro-l6u-methyl-4,6-pregnadiene- 11,3,17u,21-triol-3,20-dione2l-acetate in 390 ml. of methylene chloride, add a solution of 15.6 g.of monoperphthalic acid in 150 ml. of ether. Stir at room temperaturefor 72 hours, then add 1.5 g. of monoperphthalic acid in 15 ml. ofether. Continue stirring for 7 days, then add 20 g. of sodium bisulfitein 80 ml. of water. Stir -15 minutes. Wash the ethereal solution with 2N sodium hydroxide until the wash water remains clear. Dry the etherealsolution over sodium sulphate, then concentrate to a residue comprising60:,7oz-OXidO-9ot-fill0lO-l6- methyl-4-pregnene-1 113,l7a,21-triol-3,20-dione 21-acetate. Purify by crystallizing fromacetone/ether;

(2) In similar manner, treat 9a-fluoro-l6fl-methyl-4,6-pregnadiene-11,3,17u,21-triol-3,20-dione 21-acetate with monoperphthalicacid in methylene chloride to obtain 6u,7 xoxido 90cfluoro-16B-methyl-4-pregnene-11B, 17a,21-triol-3,20-dione 21-acetate.

(C) -6 u,7a,-oxide-9a-fluoro-16-methyl-4-pregnene-11,3,17a,2l-triol-3,20-dione 11,21-diacetate (1) To a solution of 3 g. of6oz,7u-oxido-9a-fiuoro- 16oz methyl 4 pregnene 1113,17oc,21-tli01-3,20-di0n6 2l-acetate in 30 ml. of pyridine, add 6 ml.of acetic anhydride and 150 mg. of 4-dimethylaminopyridine. Allow thereaction mixture to stay at room temperature for 18 hours. Add 10 ml. ofwater dropwise to the reaction mixture, then pour the reaction mixtureinto 600 ml. of cold water with stirring. Collect the resultantprecipitate by filtration, wash the precipitate with water, then dry invacuo at C. to give 3.13 g. (95.5% theoretical yield) of6a,7m-oxid0-9a-fluor0-16a-methyl-4-pregnene-1113,170:-2.1-triol-3,20-dione 11,21-diacetate;

(2) In similar manner, treat6u,7a-OXidO-90L-fil10l0-lfifimethyl-4-pregnene-1lfl,17u,21-triol-3,20-dione21 acetate with acetic anhydride in pyridine and 4-dimethylaminopyridineto obtain 6a,7 x-oxido-9u-fiuoro-16B-methyl-4- pregnene-l1,6,17u,21-triol-3,20-dione 11,21-diacetate;

Alternatively, the compounds of this example are also prepared byfollowing procedures D and E.

(D) 9u-fluoro-16-methyl-4,6-pregnadiene-11B,l7u,21-

triol-3,20-dione 11,21-diacetate (1) To a solution of 868 mg.9a-fluoro-16u-methyl-4,6- pregnadiene 11B,17oc,21 triol 3,20-dioneZI-acetate in 5 ml. of acetic anhydride, add 5 ml. of pyridine and stirat 50 C. for 72 hours. Cool the mixture slightly, then add about 10 ml.of water, then pour the reaction mixture into ml. of cold water. Collectthe resultant precipitate by filtration, wash the precipitate withwater, then dry in vacuo to obtain 940 mg. ofQoL-flIJOIO-lfictmethyl-4,6-pregnadiene-11,B,17a,2l-triol3,20-di0ne11,21- diacetate;

(2) Alternatively, the compound of this preparation is prepared asfollows: To a solution of 86 mg. of 9afluoro 16cc methyl4,6-pregnadiene-11fi,17a,21-triol- 3,20-dione 21-acetate in 0.5 ml. ofacetic anhydride and 0.5 ml. of pyridine, add 4 mg. of4-dimethylaminopyridine. Allow the reaction mixture to stand at roomtemperature for 3 hours, then add about 1 ml. of water. Pour thereaction mixture into 10 ml. of cold water and collect the resultantprecipitate by filtration. Dry the precipitate in vacuo to obtain 74 mg.of 9a-fll10l'O-16ctmethyl 4,6 pregnadiene 1lfi,l7a,21-triol-3,20-dione11,21-diacetate.

(3) In similar manner, treat 9a-fiuoro-l6/3-methyl-4,6-pregnadiene-1l5,17u,21-triol-3,20-dione 21-acetate with acetic anhydridein pyridine and dimethylaminopyridine to obtain9a-fluoro-16B-methyl-4,fi-pregnadiene-1 15,17, 21-triol-3,20-dione11,21-diacetate;

A231? 2.9, 4.72, 5.72, 5.80, 5.95, 6.0, 6.18, 6.2.7 and 8.1;;

In preparation 1-D (1, 2, and 3), the 21-hydroxy derivatives may be usedas starting compounds instead of the 21-monoacetate esters and therewill be formed the 11,21- diacetate products.

(E) 6a,7a-oxido-9a-fluoro-16-methyl-4-pregnene-1 113, 17 01,21-triol-3,20-dione, 1 1,21-diacetate (1) To a solution of 700 mg. of9a-fiuoro-16a-methyl- 4,6-pregnadiene 11B,17a,21 triol 3,20 dione 11,21-diacetate in 21 ml. of methylene chloride, add 8 ml. of a solution ofmonoperphthalic acid in ether (92-95 mg. monoperphthalic acid per ml.solution). Stir the reaction mixture at room temperature for 72 hours,then add 1 g. of sodium dihydrogenphosphate together with 8 ml. of ethylacetate and 8 ml. of a solution of monoperphthalic acid in ether (92-95mg. monoperphthalic acid per ml. solution). Warm the reaction mixture toreflux temperature and stir at reflux temperature for 24 hours. Add anadditional 8 ml. of a solution of monoperphthalic acid in ether (9295mg. monoperphthalic acid per ml. of solution) and continue heating thesolution at reflux temperature for 24 hours. Cool the reaction mixtureto room temperature and stir at room temperature for an additional 6days. Wash the reaction mixture successively with aqueous sodiumbisulfite, 8% sodium hydroxide and water. Dry the solution over sodiumsulphate, filter and evaporate in vacuo to a residue comprising60,7oz-OXid0-9ozfluoro 16a methyl 4 pregnene-l1B,17a,21-triol-3,20-dione 11,21-djacetate (yield=401 mg.) Purify by crystallization frommethanol to obtain 60:,7oc-OXidO-9a-flll01'0- l6a-methyl-4-pregnene-l1,8,17a,21-tri01-3,2O dione 11,21- diacetate identical to the compoundprepared in Preparation 1-C-1 hereinabove.

(2) In similar manner, treat 9a-fluoro-l6B-methyl-4,6- pregnadiene11B,17a,2l triol 3,20 dione 11,21-diacetate with monoperphthalic acid inmethylene chloride to obtain 604,7oc oxido 9a fluoro 16B methyl-4-pregnene-llfi,17a,21-triol-3,20-dione 11,21-diacetate.

PREPARATION 2 9a-chloroand Qa-bIOmO- derivatives of 6a,7a-oxido-16-methyl-4-pregnene-11B,17a,21-triol-3,2O dione 11,21- diacetate (A)9a-chlord and 9a-bIOII10- derivatives of 16-metl1yl- 4,6-pregnadiene-1113, 17u,21-triol-3 ,20-dione 2 l-acetate In a manner similar to thatdescribed in Preparation 1-A-1, treat each of the following 90: halogeno16- methyl-4-pregnenes with dichlorodicyanobenzoquinone and anhydroushydrogen chloride in dioxane:

9a-chloro-l6a-methyl-4-pregnene-l1B,17a,21-triol- 3,20-dione 21-acetate,

9a-bromo-16a-methyl-4-pregnene-1 1B,17a,21-triol- 3,20-dione 2l-acetate,and

9a-bromo-l6fi-methyl-4-pregnene-llfl,17a,2l-triol-3,20-

dione 21-acetate.

Isolate and purify the resultant respective products in a manner similarto that described in Preparation l-A-l hereinabove to obtain,respectively,

9a-chloro-l6ot-methyl-4,6-pregnadiene-1 lfi,l7u,2l-triol- 3,20-dione2l-acetate,

9a-chloro-1618-methyl-4,6-pregnadiene-1 1B,17a,21-

triol-3,20-dione 2l-acetate,

9a-bromo-16a-methyl-4,6-pregnadiene-1 1B,17a,21-triol- 3,20-dione21-acetate, and

9a-bromo- 1 6 B-methyl-4,-6-pregnadiene-1 l [3, 17u-2l-trio1- 3,20-dione21-acetate.

(B) 9a-Chl0l0- and 9a-bromoderivatives of 6oz,7a-0XidO- 16 methyl 4pregnene-l15,17u,21-triol-3,20-dione 21-acetate Treat each of the9a-halogeno-16-methyl-4,6-pregnadienes prepared in Preparation 2-Ahereinabove With monoperphthalic acid in methylene chloride in a mannersimilar to that described in Preparation 1-B-1. Isolate and purify theresultant respective products in a manner similar to that described inPreparation l-B-l to obtain, respectively,

6a,7a-oxido-9a-chloro-16a-methyl-4-pregnene- 11[3,l7oc,21-t1i0l-3,20-dione 21-acetate,

60c,7otOXidO9 a-chloro-l 6B-methyl-4-pregnene-11fl,17a,21-triol-3,20-dione 21-acetate,

60t,7d-OXIdO-90t-bl'OmO-1 6a-methyl-4-pregnene- 1 1B,17ot,21-triol-3,ZO-dione 2 1 acetate, and

6 a,7a-oxido-9a-bromo-1 65-methyl-4-pregnene-116,17a,21-triol-3,20-dione 21-acetate.

(C) 9a-Chl0f0- and 9rz-bf0m0- derivatives of 6a,7ot-oxido- 16 methyl 4pregnene-l1B,17a,21-triol-3,20-dione 11,21-diacetate Treat each of the6a,7a-oxido-9a-halogeno-16-methyl- 4-pregnene derivatives prepared inPreparation 2-B hereinabove with acetic anhydride in pyridine togetherwith 4-dimethylamino-pyridine at room temperature in a manner similar tothat described in Preparation l-C-l hereinabove. Isolate and purify theresultant respective products in a manner similar to that described inPreparation 1-C-l to obtain, respectively,

60,7cL-OXIdO-9oc-Chl0l0- 1 6a-methyl-4-pregnenel1,B,l7oc,2l-Ii0l-3,20-dione 11,21-diacetate, 6a,7a-oXido-9a-chloro-16/3-methyl-4-pregnene-11,8,17u,21-triol-3,20-dione 11,21-diacetate, 6 a,7a-oxido-9a-br0mo-16u-methyl-4-pregnenel1,B,l7a,21-triol-3 ,20-dione 11,21-diacetate, and611,7 u-oxido-9 a-bromol 63-methyl-4-pregnene- 11,8,17a,21-triol-3,20-dione 11,21-diacetate.

PREPARATION 3 Other 6a,7 a,oxido-1 1B-acetoxy-4-pregnene-3,20-dioneintermediates Other 6a,7a-oxido-11B-acetoxy-4-pregnene-3,20-dionesutilized as starting compounds in the examples which follow are preparedin a manner similar to that described in Preparation 1.

PREPARATION 4 6a,7a-oxido-1 1B,17u-diformyloxy-2l-acetoxy-4-pregnene-.3,20-diones (A) 9a-fluoro-16ot-methyl-4,6-pregnadiene-1113,17a,21- triol-3,20-dione 11,17-diformate 21-acetate (1) To asolution of 2.0 g. of 9oc-fi11010 16a methyl- 4,6 pregnadienell,B,l7a,2l triol 3,20 dione 21- acetate in 30 ml. of formic acid(98l00% add 200 mg. of p-toluenesulfonic acid. Stir at room temperaturefor 20 hours, then pour the reaction mixture into 600 ml. of cold water.Collect the resultant precipitate by filtration, wash the precipitatewith water and air dry to give 9a-fll101'0- 16a methyl 4,6 pregnadiene11B,17a,21 triol-3,20- dione, 11,17-diformate 21-acetate.

(2) In similar manner treat each of 9a-fluoro-16fimethyl 4,6 pregnadiene1lfi,17oc,21 triol 3,20-dione 21 acetate and 4,6 pregnadiene11,3,17a,21-tri0l-3,20- dione 21-acetate with formic acid in thepresence of ptoluenesulfonic acid to obtain, respectively,9a-fl110IO-16f3- methyl 4,6 pregnadiene 1l,B,17a,21 triol 3,20-dione11,17-diformate 21-acetate, and 4,6-pregnadiene-11B,17a,21-triol-3,20-dione 11,17-diformate 21-acetate.

(3) In the above procedures, by utilizing the free trihydroxy compoundas starting material, there is obtained a corresponding triformateester, i.e., 9a-fluoro-16amethyl 4,6 pregnadiene 11;3,l7u,21 triol3,20-dione 11,17,21-triformate, and a fluoro 16f! methyl 4,6-pregnadiene 11,8,17a,21 triol 3,20 dione 11,17,21- triformate.

(B) 60,7ot oxido 9oz fluoro 16a methyl-4-pregnene11,8,17a,21-triol-3,20-dione 11,17-diformate 21-acetate (1) To asolution of 1 g. of 9a fluoro 16a methyl- 4,6-pregnadiene-3,20-dione11,17-diformate ZI-acetate in 50 ml. of methylene chloride, add asolution of 95 mg. monoperphthalic acid in 10 ml. of ether. Stir thereaction mixture at room temperature for 8 days, then filter thereaction mixture. Wash the filtrate with aqueous sodium bisulfatesolution, then with three portions of dilute sodium hydroxide (3%) andfinally with water. Dry the ethereal solution with sodium bisulfate andthen concentrate to a residue comprising 6a,7a-oxido-9u-fluoro-16amethyl4 pregnene-l15,17u,21-triol-3,20-dione 11,17- diformate 21-acetate.Purify by recrystallization from acetone-hexane.

(2) In similar manner, treat each of the115-formyloxy-4,fi-pregnadiene-3,20-diones prepared as described inPreparation 4-A-2 with monoperphthalic acid in methylene chloride.Isolate and purify the resultant respective products in a manner similarto that described to obtain, respectively.

6a,7a-oxido-9a-fiuoro-165-methyl-4-pregnene-1 15,17a,21-

triol-3,20-dione 11,17-diformate 21 acetate, and

6a,7a-oxido-4-pregnene-115,17a,21-triol-3,20-dione 11,

17-diformate ZI-acetate.

(3) In similar manner, treat each of the 9u-fluoro-16-methyl-4,6-pregnad-iene-115,17a,21-triol-3,20-dione 1 1,17-21-triformates prepared in Example 4-A-3 with monoperphthalic acid inmethylene chloride to obtain, respectively,

6a,7a-oxido-9u-fluoro-l6a-methyl-4-pregnene-1 1/8,17oc,21-

triol-3,20-dione 1 1,17,21-triformate, and

6a,7a-oxido-9a-fluoro-165-methyl4-pregnenel l5,17oc,2l-

triol-3,20-dione 11,17,21-triformate.

PREPARATION 5 6a,7a-oxido-9a-fluoro-16-methyl-4-pregnene-l 15,1711-21-trio1-3,20-dione ll-trifluoroacetate 21-acetate To a solution of 100 mg.of60:,7a-0XidO-90t-flUOIO-l60amethyl-4-pregnene-115,17a,21-triol-3,20-dione21-acetate in 1 ml. of pyridine at --10 C., add 0.4 ml. oftrifluoroacetic anhydride. Allow the solution to stand at roomtemperature for two hours, then pour the reaction mixture into diluteaqueous hydrochloric acid containing 1.4 ml. of concentratedhydrochloric acid. Collect the resultant precipitate by filtration, washthe precipitate with water, then dry in vacuo at 80 C. to give6a,7a-OXidO-9a-flu01'0-16a-methyl-4-pregnene-1l5,17a,21-trio1-3,20-dione 1 l-trifluoroacetate21-acetate.

In similar manner treat 6a,7a-oxido-9a-fluoro-165- methyl-4-pregnene-115,17a,21-triol-3,20-dione 21-acetate with trifiuoroacetic anhydride inpyridine at 10 C. there is obtained 6a,7a-oxido-9a-fluoro-165-methyl-4-pregnene-l15,17a,21-triol-3,20-dione 11 trifluoroacetate 21-acetate.

EXAMPLE 1 6-azido-9a-fluoro-16-methyl-4,6-pregnadiene-115,17a,21-triol-3,20-dione (A) 65-azido-9a-fluoro-16-methyl-4-pregnene-7a,115,17a,21-tetrol-3,20-dione 11,2l-diacetate 1) To a solution of 3.0 g. of6u,7a-oxido-9a-fluoro- 16a-methyl-4-pregnene-115,17a,21-tl'iOl-3,20-di0l16 1 1,21- diacetate in 300 ml. of methanol and30 ml. of water under an atmosphere of argon, add 9 g. of sodium azidefollowed by 9 ml. acetic acid and stir the reaction mixture in theabsence of light at 3035 C. under an argon atmosphere for 70 hours. Addan additional 3 g. of sodium azide and 3 ml. of acetic acid and continuestirring at 3035 C. for an additional 44 hours. Evaporate the reactionmixture to a small volume in a current of nitrogen, then pour theresidue into water. Saturate the resulting aqueous suspension withsodium chloride and separate the resultant precipitate by filtration,wash the precipitate with water, then dry the precipitate in vacuo at 50C. to give 65 azido-9a fluoro-16a-methyl-4-pregnene-7a,115,

20 17a,21-tetrol-3,20-dione 11,21-diacetate; yield=2.96 g. (90.8%theory);

This product is used without further purification as starting compoundin Example l-B hereinbelow.

(2) In similar manner, treat 6a,70c,0Xid0-9oL-fill0rO-165-methyl-4-pregnene-1 15,17a,21-triol-3,20-dione 1 1,21- diacetate inaqueous methanol with sodium azide at 30- 35 C. in the absence of lightto obtain 65-azido-9u-fluoro- 165-methyl-4-pregnene-7 11,1 1 5, 1 711,21-tetrol-3,20-dione 11, ZI-diacetate in 95.4% theoretical yield.

(B) 65-azido-9a-fluoro-16-methyl-4-pregnene-7a,115,1711,2l-tetrol3,20dione 7,11,2l-triacetate (1) To a solution of 2.8 g. of65-azido-9a-fluoro-l6amethy1-4-pregnene-7a,1 15,l7a,21-tetrol-3,20-dione 11,21- diacetate in 28 ml. of pyridine cooledto 15 C. and under an argon atmosphere, add 6 ml. of acetic anhydrideand mg. of 4-dimethylaminopyridine. Allow the reaction mixture to remainat 5 C. for 20 hours in the absence of light. Add a small amount ofwater, then pour the reaction mixture into 600 ml. of ice water.Saturate the aqueous mixture with sodium chloride, then separate theresultant precipitate by filtration. Wash the precipitate with water,dry in vacuo at 60 C. to give 2.51 g. (83% theory) 65 azido 9ozfluoro-l6a-methyl-4-pregnene-7a, 115,l7oc,2l-tetrol-3,20-dione7,11,21-triacetate;

This compound is used without further purification as an intermediate infollowing Example l-C.

(2) In similar manner, treat a pyridine solution of 65- azido 9a fiuoromethyl 4 pregnene 7oz, 11,8,17oc-21-l6tl01-3,20-di011 11,21-diacetatewith acetic anhydride and dimethylaminopyridine to obtain 65-azid0- 9afluoro-165-methyl-4-pregnene-7a,l15,17a,21-tetrol-3, 20-dione7,11,21-triacetate in 81.5% theoretical yield.

(C) 6-azido-9a-fluoro-16-methyl-4,6-pregnadiene-1 15,17a,21-triol-3,20-dione 11,21-diacetate (1) Concentrate to dryness in vacuoa solution of 4.8 g. of tetramethylammoniumfiuoride penta-hydrate in 96ml. of acetonitrile. Then add 2.4 g. of 65-azido-9a-fluoro- 16u-methyl 4pregnene-7a,115,17a,21-tetrol-3,20-dione 7 ,11,21-triacetate and 96 ml.of acetonitrile. Stir the reactron mixture under an argon atmosphere inthe absence of light and at room temperature for 40 hours. Pour thereaction mixture into one liter of cold water, saturate the aqueousmixture with sodium chloride and separate the resultant precipitate byfiltration. Wash the precipitate with water and air dry to give 2.0 g.of a precipitate comprising6-azido-9a-fiu'oro-16a-methyl-4,6-pregnadiene-1 15,17a,2l-ll'iOl-3,20-dl0l'l6 11,21-diacetate. Purify by dissolving inchloroform and chromatographing on 115 g. of Florisil (hexane washed).Develop the column by successively using 200 ml. portions of hexane,methylene chloride and 0.5% methanol in methylene chloride. Combine the2nd and 3rd 0.5 methanol in methylene chloride fractions and evaporateto a residue comprising 0.53 g. of6-azido-9a-fluoro-16a-methyl-4,6-pregnadiene-115,17a,21-triol-3,20-dione 11,2l-diacetate;

mew 24s and 295 mp. $13,500, 11,300);

a ,"'+11e.2 (dioxane) 21 diacetate. Evaporate the like fractions to aresidue to give an additional 0.14 g. of product making the total yieldof purified6,6-azido-9a-fluoro-16a-methyl-4,6-pregnadiene-l1/5',17a,21-triol-3,20-dione11,21-diacetate=0.67 g. (31.1% theoretical yield).

(2) In similar manner, treat 6,3-azido-9a-flu0r0-16f3- methyl-4-pregnene711,11p),l7u,21-tetrol-3,20-dione 7,11, 21-triacetate in acetonitrilewith tetramethylammoniumfluoride to obtain6-azido-9u-fluoro-16fl-methyl-4,6-pregnadiene-11fi,17a,21-triol 3,20dione 11,21-diacetate in 48.6% theoretical yield;

AER? 2.9, 4.72, 5.72, 5.80, 5.95, 6.0, 6.18, 6.27, 8.1a

(D) 6-azido-9a-fiuoro-16u-methyl-4,6-pregnadiene-11B,l7u,21-triol-3,20-dione (1) Place in each of eight 300 ml. cultureflasks 100 ml. of prepared medium composed of 10 g. Difco yeast extract,4.49 g. of potassium dihydrogen phosphate and 8.84 g. of disodiumhydrogen phosphate per 1000 ml. of sterile distilled Water, add a 1 ml.inoculum of Flavobacterium dehydrogenans, var. hydrolyticum (ATCC13930), and incubate at 30 C. on a rotary shaking machine. After a24-hour growth period, add to each of the eight flasks a 2 ml. portionof a solution of 0.21 g. of6-azido-9a-fluoro-16a-methyl-4,6-pregnadiene-115,17a,2l-triol-3,20-dione 11,21-diacetate in 16 ml. of ethanol and continueincubation for an additional 23 hours. At the end of the incubationperiod, pool the broths and extract with chloroform. Evaporate thecombined extracts in vacuo to a residue. Dissolve the residue in 20 ml.of chloroform and percolate the chloroform solution through achromatographic column containing 30 mg. of Florisil (hexane washed).Develop the column using chloroform and 5% methanol in chloroform.Combine the 5% methanol in chloroform eluates and evaporate in vacuo toa residue comprising 0.157 g. of6-azido-9u-fiuoro-16amethyl-4,6-pregnadiene-11,6,l7a,21-triol-3,20-dione (88% theoretical yield). Purify bycrystallization from acetone;

32 249 and 296 my (e=12,300 and 10,650); [odiF-l- 109.1 (dioxane) (2) Insimilar manner, subject 6-azido-9a-fluoro-16flmethyl-4,6-pregnadiene-11fl,17oc,21-tIiO1-3,20-di0116 11,21- diacetate to the action ofFlavobacterium dehydrogenans, var. Hydrolyticum (ATCC 13930); isolateand purify the resultant product in a manner similar to that describedto obtain 6-azido-9a-fluoro-16a-methyl-4,G-pregnadiene- 113,l7zx,21-tliOl-3,20di0l16;

EXAMPLE 2 6p-azido-9a-fiuoro-16a-methyl-4-pregnene-7ot,1 15,121,21-tetro1-3,20-dione 21-acetate ANuiol max.

Add 9 g. of sodium azide and 9 ml. of acetic acid to a solution of 1.5g. of6u,7x-oxido-9ot-fluoro-16amethyl-4-pregnene-11B,17a,21-triol-3,20-dione2l-acetate in 225 ml. of methanol and 45 ml. of water under anatmosphere of argon. Stir the reaction mixture at room temperature inthe absence of light for 5 days. Add an additional 1.5 g. of sodiumazide and 1.5 ml. of acetic acid and continue stirring at roomtemperature under an atmosphere of argon for an additional 5 days.Evaporate the reaction mixture in a stream of nitrogen and slurry theresultant residue with water, then extract with ethyl acetate. Wash thecombined extracts with water, dry the combined ethyl acetate extractsover sodium sulphate, and evaporate in vacuo to a residue (2.1 g.).Dissolve the residue in chloroform and place on 10 preparativechromatographic plates (10" x 10" and containing a 2000 thickness ofsilica-gel). Dry the plates at room temperature using nitrogen gas, thendevelop the plates in a glass tank containing chloroform-ethyl acetate(2:1) solvent system. Remove the more polar zone of the resulting twozones and extract repeatedly with portions of warm chloroform and Warmethyl acetate. Evaporate the combined extracts to a residue (600 mg.).Dissolve the residue in chloroform and rechromatograph on silica-gelchromatographic plates, dried and developed in the same manner asdescribed hereinabove. Extract the resulting tWo zones separately withsuccessive portions of warm chloroform followed by ethyl acetate.Concentrate the combined extracts of each zone to dryness: Zone A:220mg. and Zone B= mg. Identify each zone by thin layer chromatography; ifthin layer chromatograph identifies each zone as a mixture of compounds,combine the zones in chloroform and rechromatograph on thick silica-gelplates. Develop the plates with chloroform-ethyl acetate (2:1) until aseparation into three zones is obtained. Extract the middle zone withsuccessive portions of hot chloroform, ethyl acetate and acetone,combine the eluates and evaporate to a residue comprising 40 mg. (2.45%theory) of 6B-azido-9afiuoro-l6u-methyl-4-pregnene-7a,11fl,17a,21-tetrol3,20- dione 21-acetate;

ggihnnoi m (e:

EXAMPLE 3 6-azido-9a-chloro-16-methyl 4,6 pregnadiene 1118,17a,

21-trio1-3,20-dione and 6-azido-9a-bromo-16-methyl-4,6-pregnadiene-11,8,17a,21-triol-3,20-dione (A) 9a-chloro and9a-bromo-derivatives of 6l3-azido-16- methyl-4-pregnene 7a,11}3,17u,21tetrol 3,20 dione 11,21-diacetate In a manner similar to that describedin Example 1-A-1, treat each of the following6a,7a-oxido-9a-halogeno-llfi-acetoxy-4-pregnenes with sodium azide inaqueous methanol under an atmosphere of argon:

611,7 oz-OXidO-90t-ChlOfO-1 6u-methyl-4-pregnene-1 118,170

21triol-3,20-dione 11,21-diacetate,6a,7a-oxido-9a-chloro-16,8-methyl-4-pregnene-1 1 53,1711,

21-triol-3,20-dione 11,21-diacetate, 6u,7a-oxido-9x-bromo-16a-methyl-4-pregnene-1 1 B, 17 a,

2 l -triol-3,20-dione 11,21-diacetate, and6u,7u-oxido-9a-bromo-16f3-methyl-4-pregnene-1 15,170,

21-triol-3-,20-dione 11,21-diacetate.

Isolate and purify the resultant respective products in a manner similarto that described in Example 1-A-1 to obtain, respectively,

6fl-azido-9ot-chloro-16u-methyl-4-pregnene17a,11fi,17u,

21-tetrol-3,20-dione 1 1,21-diacetate,

6fl-azido-9 u-chloro- 1 6;3-methyl-4-pregnene-7u, 1113,1711,

21-tetro1-3,20-dione 11,21-diacetate,

6B-azido-9a-bromo-16a-methyl-4-pregnene-7a,1 113, 17a,

21-tetrol-3,20-dione 11,21-diacetate, and

Gfl-azido-Qu-bromo-16fi-methy1-4-pregnene-7a,1 1,8,17u,

21-tetrol-3,20-dione 11,21-diacetate.

(B) 9u-chloroand 9a-bromo-derivatives of 6fi-azido-16-methyl-4-pregnene-7a,11,6,17a,21 tetrol 3,20 dione 7,1 1,21-triacetateIn a manner similar to that described in Example 1-B-1, treat each ofthe 6 3-azido-7a-hydroxy-9a-halogeno-16-methyl-4-pregnenes prepared inExample 3-A with acetic anhydride in pyridine under an atmosphere ofargon. Isolate and purify the resultant respective products in a mannersimilar to that described in Example 1B-1 to obtain, respectively,

ANuiol max.

23 (C) 9a-chloroand 9a-bromo-derivatives of 6-azido-16-methyl-4,6-pregnadiene-1113,17a,21 triol 3,20 dione 11,21-diacetate -Ina manner similar to that described in Example l-C, treat each of the 63-azido-7a-acetoxy-9a-halogeno-l6- methyl-4-pregnenes prepared inExample 3-B with tetramethylammonium fluoride pentahydrate inacetonitrile. Isolate and purify the resultant respective products in amanner similar to that described in Example 1-C to obtain, respectively,

6-azido-9a-chloro-16u-methyl-4,6-pregnadiene-1 1 5,1702,

21-tri0l-3,20-dione 1 1,21-diacetate,6-azido-9a-chloro-16,8-methyl-4,G-pregnadiene-115,170

2l-triol-3,20-dione 1 1,21-diacetate,6-azido-9a-bromo-l6u-methyl-4,6-pregnadiene-1113,17a,

21triol-3,20-dione l l,21-diacetate,' and6-azido-9a-bromo-16fl-methyl-4,6-pregnadiene-115,17,

21-triol-3,20-dione 1 1,21-diacetate.

(D) 9oz-Chl01'0- and 9a-bromo-derivatives of 6-azido-16-methyl-4,6-pregnadiene-1 1/8,17a,21-triol-3,20-dione In a manner similarto that described in Example l-D-l, subject each of the6-azido-115,21-diacetoxy-16- methyl-4,6-pregnadienes prepared in Example3-C to the action of the microorganisms Flavobacterium delzydrogenansvar. Hydrolyticum (ATCC 13930). Isolate and purify the resultantrespective products in a manner similar to that described in Example1-D-1 to obtain, respectively,

6-azido-9u-chloro-16a-methyl-4,6-pregnadiene-1113,17,

21-triol-3,20-dione,

6-azido-9a-chloro-16fl-methyl-4,6-pregnadiene-115,17a,

2l-triol-3,20-dione,

6-azido-9a-bromo-16a-methyl-4,6-pregnadiene-1 15,17,

21-triol-3,20-dione, and

6-azido-9a-bromo-16fi-methyl-4,6-pregnadiene-1 15,17,

21-triol-3,20-dione.

EXAMPLE 4 6-azido-4,6-pregnadiene-1 1/8,17a,21-triol-3,20- dione21-acetate (A) 6B-azido-4-pregnene-7u,l1{3,17a,21-tetrol- 3,20-dione11,21-diacetate To a stirred solution of 100 mg. of6a,7a-oxido-4-pregnene-l1B,17a,21-triol-3,20-dione 11,21-diacetate in 4ml. of methanol, 2 ml. of dioxane, and 1 ml. of water, add 300 mg. ofsodium azide followed by 0.3 ml. of acetic acid. Stir the reactionmixture in the absence of light at 30-35 for 18 hours. (After threehours of reaction time, an aliquot of the reaction mixture analyzed bythin layer chromatography and infra-red spectroscopy indicates about 30%conversion of the 6a,7a-oxido-4-pregnene to the6fi-azido-7-hydroxy-4-pregnene.) Add 10 ml. of water to the reactionmixture, then evaporate the mixture in a current of nitrogen to acrystalline mass comprising 6/3- azido-4-pregnene7u,1113,l7a,21-tetrol-3,20-dione 11,21- diacetate. Collect by filtrationthe crystalline mass, wash with water, then dry the residue in vacuo togive 98 mg. (90% theory) of6B-azido-4-pregnene-7u,1lp,17a,2ltetrol-3,20-dione 11,21-diacetate;

32 233 mp (e=11,700) [a f+102.1 (dioxane) This product is used withoutfurther purification as starting compound in Example 4-B hereinbelow.

(B) 6fl-Azido-4-pregnene-7a,1 1p, 170c,21-t6tf013,20-di01167,11,21-esters (1) The 7,11,21-triacetate.In a manner similar to thatdescribed in Example l-B, treat 6fi-azido-4-pregnene-7a,1118,l7ot,2l-tetrol-3,20-dione 11,2l-diacetate with acetic anhydridein pyridine in the presence of 4-dimethylamino- 24 pyridine. Isolate andpurify the resultant product in a manner similar to that described toobtain 6B-azido-4-pregnene-7a,1 1,8,17a,21-tetrol-3,20-dione7,11,21-triacetate.

(2) The 7-methanesulfonate 11,21-diacetate.To a solution of 3 g. of6fi-azido-4-pregnene-7a,11B,17a,21-tetrol- 3,20-di0ne 11,21-diacetate in30 ml. of pyridine, add 1.5 m1. of methanesulfonyl chloride. Allow thereaction mixture to stand at room temperature for 17 hours, then pourthe reaction mixture into cold water and collect by filtration theresultant precipitate comprising6fi-azido-4-pregnene-7a,11p],17a,21-tetrol-3,20-dione 7 methanesulfonate11,21-diacetate. Dry the precipitate in vacuo and use Without furtherpurification in the procedure of Example 4-0.

In the above procedure, by utilizing 1.8 g. of p-tolue'nesulfonylchloride in place of the 1.5 ml. of methane-sulfonyl chloride, there isobtained the corresponding 7-ptoluenesulfonate ester.

(C) 6 azido 4,6 pregnadiene 1l/3,17oc,21 triol- 3,20-dione11,21-diacetate.In a manner similar to that described in Example l-C,treat each of 6fi-azido-4-pregnene-7a,l1B,l7a,21-tetrol-3,20-dione7,11,21 triacetate and6p-azido-4-pregnene-7a,11p,17a,21-tetrol-3,20-dione 7-methanesulfonate11,21-diacetate with tetramethylammonium fluoride pentahydrate inacetonitrile. Isolate and purify the respective resultant products in amanner similar to that described in Example 1-C to obtain, from bothstarting compounds, 6-azido-4,6pregnadiene-1113, l7u,2l-triol-3,20-dione11,21-diacetate.

(D) 6-azido-4,6-pregnadiene-11B,17a,21-triol-3,20-dione In a mannersimilar to that described in Example l-D, subject 6 azido4,6-pregnadiene-11p,l7u,21-triol-3,20- dione 11,21-diacetate to theaction of Flavobacterium dehydrogenans. Isolate and purify the resultantproduct in a manner similar to that described in Example l-D to obtain6-azido-4,6-pregnadiene-11 8,17a,21-triol-3 ,20-dione.

(E) 6-azido-4,6-pregnadiene-1 1p,17u,21-trio1-3,20-dione 2 l-acetate Add0.2 ml. of acetic anhydride to a solution of 100 mg. of6,8-azido-4,6-pregnadiene-115,17u,21-triol-3,20dione in 1 ml. ofpyridine and allow the reaction mixture to stand at room temperature for18 hours. Pour the reaction mixture into 100 ml. of ice water and stirfor 20 minutes. Collect the insoluble fraction by filtration, dry invacuo and crystallize from acetone to obtain 6-azido-4,6-pregnadiene-l113,17a,21-triol-3,20-dione 21-acetate;

EZZ 251 E'. 299 M (=12,452); 5 (CD01 0.73, 1.31, 2.15, 3.38, 4.66, 5.13,5.78, 6.12 pp iff-P20? (dioxane) EXAMPLE 56/3-azido-4-pregnene-7a,11B,17a,21-tetrol-3,20-di0ne 2 l-acetate To asolution of 100 mg. of 6a,7u-oxido-4-pregnene-1118,17a,21-triol-3,20-dione 21-acetate in 2 ml. dioxane and 4 ml.methanol, add a solution of 300 mg. of sodium azide in 1 ml. of waterand 0.2 ml. of acetic acid. Allow the reaction mixture to stand at roomtemperature. At the end of 18 hours an aliquot of the reaction mixtureanalyzed by thin layer chromatography and infra-red spectroscopyindicated about 30% conversion of the 6a,7a-oxido-4- pregnene to the6-azido-7a-hydroxy-4-pregnene. Allow the reaction mixture to remain atroom temperature for 4 days, then pour the reaction mixture into waterand extract with chloroform. Dry the chloroform solution over magnesiumsulphate and evaporate the solution to a residue comprising6,8-azido-4-pregnene-7oz,11}3,17u,2l-triol-3, 20-dione ZI-acetate;yield-: mg. (68% theory). Purity by recrystallization from ethyl ether,[a] +91 (dioxane).

( l) 6-azido-16-chloromethylene-4,6pregnadiene-1 1,6,

l7a-diol-3,20-dione,

( l 1 6-azido-16a-methyl-4,6pregnadiene-1 15,170:-

3,20-dione,

( 12) 6-azido-16p-methyl-4,6-pregnadiene-1 118,170-

diol-3,20-dione, and

( 13) 6-azido-4,6-pregnadiene-1 1,8-ol-3,20-dione.

'EXAMPLE 8 Preparation of 21unsubstituted-6-azido-4,6-pregnadienes from21-acetoxy-6-azido4,6-pregnadienes (A) 6-azido-11B-acetoxy-4,6-pregnadiene- 21-o1-3,20'-di0nes (1) To a solution of0.486 g. of 6-azido-9a-fluoro-4,6- pregnadiene-llfi,17a,21-triol-3,20-dione 11,21-diacetate in 14.4 ml. methanol, adddropwise 1.1 ml. of 1 N aqueous sodium hydroxide over a half-hour periodwhile stirring the solution. Continue stirring at room temperature foranother 1.5 hours, then neutralize by adding acetic acid dropwise. Pourinto 100 ml. of water and concentrate the reaction mixture in vacuo to avolume of about 25 ml. Cool the aqueous reaction mixture, filter theresultant precipitate, then wash the filtered residue with water and airdry to obtain 6-azido-9afiuoro-4,6-pregnadiene11,3,l7a21-tri01-3,20-dione ll-acetate. This product is used without furtherpurification in the procedure described in Example 8-B hereinbelow.

(2) In a manner similar to that described in Example 8A-1 hereinabove,treat each of the following 6-azido- 1113,21diacetoxy-4,6-pregnadienesin aqueous methanol with 1 N aqueous sodium hydroxide:

6-azido-9a-fiuoro-16u-methyl-4,6-pregnadiene-l 15,1711,

21-triol-3,20-dione 1 1,2l-diacetate,

6-azido-9u-fiuoro-16fl-methyl-4,6pregnadiene-1lfl,l7a,

21-triol-3,20-dione 1 1,21-diacetate,

6-azido-9a-flnoro-16-methylene-4,G-pregnadiene-1113,17a,

21-triol-3,20-dione 11,21-diacetate,

6-azido-9a-fluoro-16u,17a-isopropylidenedioxy-4,6-pregnadiene-l 15,21-diol-3,20-dione 1 1,21-diacetate, and

6-azido-4,6-pregnadiene-1113,17a,21-triol-3,20-dione ll-2l-diacetate.

Isolate and purify the resultant respective products in a manner similarto that described in Example 8A-1 to obtain, respectively,

6-azido-9u-finoro-16ot-methyl-4,6-pregnadiene-1 119,17,

21-triol-3,20-dione 1 l-acetate,6-azido-9u-fiuoro-16l3-methyl-4,6pregnadiene-1 1,8,17a,

21-triol-3,20-dione 1 l-acetate,6-azido-9ufluoro-16-methylene-4,fi-pregnadiene-1 13,170

21-triol-3 ,ZO-dione 1 l-acetate,6-azido-9a-fluoro-16a,l71u-isopropylidenedioxy-4,fi-pregnadiene-l1B,21-diol-3,20-dionel l-acetate, and 6-azido-4,6-pregnadiene-1 1B,1l7a,2 1-trio1-3,20-dione1 l-acetate.

(B 6-azido-1 1 B-acetoxy-Z l-methanesulfonyloxy-4,6-pregnadiene-3,20-diones (1) To a solution of 5 g. of6-azido-'9a-fluoro-4,6-pregnadiene-l1,6,17a,21-triol-3,20-di0nell-acetate in 50 ml. of pyridine cooled to (3., add dropwise 5 ml. ofmethanesulfonyl chloride. Stir at 20 C. for minutes, then pour intowater and stir for two hours longer at room temperature. Filter and drythe resultant precipitate comprising6-azido-9a-fluoro-4,6-pregnadiene-1lp,l7a,2ltriol-3,20-dione ll-acetate21-methanesulfonate.

(2) In a manner similar to that described in Example 8B-1 hereinabove,treat each of the fi-azido-llfiacetoxy-4g6-pregnadiene-21-ol-3,20-dione's prepared as described inExample 8A-2 hereinabove with methanesulfonyl chloride in pyridine.Isolate and purify the resultant respective products in a manner similarto that described hereinabove to obtain, respectively,

6-azido-9u-fluoro-16a-methyl-4,6-pregnadiene-1 113,17,

21-triol-3,20-dione 1 l-acetate ZI-methanesulfonate,

6-azido-9'ct-fluoro-1 6fl-methyl-4,6-pregnadiene-1 1p, 17 a,

21-triol-3 ,20-dione 1 l-acetate 21-methanesulfonate,

6-azido-9'ot-fluoro-16-methylene-4,6pregnadiene-1 119,17,21-trio1-3,20-dione 1 1-acetate 21-methanesulfonate,

6-azido-9u-fluoro-16a,17a-isopropylidenedioxy-4,'6-

pregnadiene-l1fi,21-diol-3,20-dione 1 1 acetate 21-methanesulfonate, and

6-azido-4,6-pregnadiene-l 1 18,1? u,21-triol-3,20-dione 1 l-acetate21-methanesulfonate.

(C) 6-azido-11B-acetoxy-21-iodo-4,6-pregnadiene- 3,20-diones (1) To 3.5g. of 6-azido-9a-fluoro-4,fi-pregnadiene-11p, 17a,2l-trio1-3,20-dionell-acetate ZI-methanesulfonate in 52.5 ml. of acetone, add 3.5 g. ofsodium iodide. Heat the reaction mixture at reflux temperature for 20minutes, then pour into 500 ml. of water, filter and air dry to aresidue comprising 6-azido-9a-fluoro-2l-iodo-4,6-pregnadiene-l1B,17u-diol-3,20-dione 1 l-acetate.

(2) In a manner similar to that described in Example 8C-1, treat each ofthe 6-azido-1lfi-acetoxy-Zl-methanesulfonyloxy-4,-6-pregnadienesprepared as described in Example 8-B-2 with sodium iodide in acetone.Isolate and purify the resultant respective products in a manner similarto that described in Example 8B-2 to obtain, respectively,

6-azido-9u-fluoro-21iodo-1&6u-methy1-4,6-pregnadiene-11p,17ot-dio1-3,20-dione ll-acetate,6-azido-9u-fiuoro-21-i0do-16p-methyl-4,6-pregnadiene- 11B,17a-di0l-3,20-di0n6 1 1-acetate, 6-azido-9a-fluoro-2l-iodo-16-methylene-4,fi-pregnadiene- 1 1,9, 17 a-diOl-3 ,20-dione 1l-acetate, 6-azido-9a-fluoro-21-i0do-1,6u,17a-isopropylidenedioxy-4,6-pregnadiene-1 15-01-3 ,20-dione 1 l-acetate, and6-azido-21-iodo-4,6-pregnadiene-l 1,8,17a-dio1-3,20-dione 1 l-acetate.

(D) 6-azido-1 1,8-acetoxy-21-unsubstituted-4,6- pregnadiene-3,20-diones(1) To a refluxing solution of 1 g. of 6-azido-9a-fluoro- 21iodo-4,6-pregnadiene-11B,17a-diol-3,20-dione ll-acetate in 20 ml. ofmethanol, add a solution of 3 g. of sodium bisulfite in 10 ml. of water.Stir the reaction mixture at reflux temperature for 30 minutes, thenconcentrate in vacuo to a crystalline slurry. Dilute the slurry with 20ml. of water and collect the crystalline precipitate by filtration. Washthe precipitate with hot water, then dry in vacuo to give6azido-9afluoro-4,6-pregnadiene-11p, 17a-diol-3,20-dione ll-acetate.Purify by crystallization from acetone-hexane.

(2) In a manner similar to that described in Example 8-D-1 hereinabove,treat each of the 6-azido-11fi-acetoxy-21-iodo-4,6-pregnadienes preparedas described in Example 8-C-2 in methanol with aqueous sodium bisulfite.Isolate and purify the resultant respective products in a manner similarto that described to obtain, respectively,

6-aZldO-9OL-flUOI'O 1 6a-methyl-4,6-pregnadiene-1 113,171;-

diol-3 ,20-dione 1 l-acetate,6-azido-9a-fluoro-16fl-methyl-4,6-pregnadiene-l 15,17-

diol-3,20-dione 1 l-acetate,6-azido-9u-fluoro-16-methylene-4,6-pregnadiene-1113,170:-

diol-3,20-dione ll-acetate,6-azido-9a-fiuoro-16u,17a-isopropylidenedioxy-4,6-pregnadiene-l1B-ol-3,20-dione 1 l-acetate, and 6-azido-4,6-pregnadiene-1 1 9, 17oz-diOl-3 ,20-d one 1 l-acetate.

(E) 6-azido-11,8-hydroxy-21-unsubstituted-4,6- pregnadiene-3,20-diones(1) In a manner similar to that described in Example 1-D, subject6-azido-9a-fluoro-4,6-pregnadiene-l1 6,170:- diol-3,20-dione ll-acetateto the action of F lavobacterium dehydrogenans (ATCC 13930). Isolate andpurify the resultant respective products in a manner similar to thatdescribed in Example 1-D to obtain 6-azido-9a-fluoro- 4,6-pregnadiene-11B, 17a-di01-3 ,20-dione.

(2.) In a manner similar to that described in Example 8-E-1 hereinabove,subject each of the6-azido-1lfl-acetoxy-Zl-unsubstituted-4,6-pregnadienes prepared inExample 8-D-2 to the action of Flavobacterium dehydrogerzans. Isolateand purify the resultant respective products m a manner similar to thatdescribed hereinabove to obtain, respectively,

6-azido-9a-fluoro-l 6a-methyl-4,6-pregnadiene-1 15,17u-

diol-3,20-dione, 6-azido-9a-fiuoro-16fl-methyl-4,6-pregnadiene-115,170:-

diol-3 ,20-dione, 6-azido-9u-finoro-16-methylene-4,6-pregnadiene- 113,17a-diol-3,20-dione, 6-azido-9a-fluoro-16a,17a-isopropylidenedioxy-4,6

pregnadiene-l1B-ol-3,20-dione, and6-azido-4,6-pregnadiene-115,17et-di0l-3 ,20-dione.

EXAMPLE 9 21-halogeno-6-azido-4,6-pregnadiene-3 ,20-diones (A)6-azido-9a-fiuoro-21-ha1ogeno-4,fi-pregnadiene- 11 13,17a-dil-3,20-di0n6ll-acetate (1) To 0.5 g. of6-azido-9a-fiuoro-2l-iodo-4,6-pregnadiene-l1fi,17a-diol-3,20-dionell-acetate (compound of Example 8-'C1) in 100 ml. of acetonitrilecontaining 1 ml. of Water, add 1.76 g. of silver chloride in a 50%aqueous solution. Warm the mixture at 30-40 C. for four hours, thenfilter and pour the filtrate into water. Filter the resultantprecipitate comprising 6-azido-9afluoro-21-chloro 4,6 pregnadiene11fi,17a-diOl-3,20-dione ll-acetate.

(2) The above procedure by substituting for silver chloride anequivalent quantity of silver fluoride or silver bromide, there isobtained the corresponding 21-fiuoride or 2l-bromide derivative, i.e.6-azido-9u,21-difluoro-4,6- pregnadiene-l113,l7a-diol-3,20-dionell-acetate and 6-azido-9a-fluoro 21 bromo 4,6-pregnadiene-l15,17vt-di0l-3,20-dione ll-acetate, respectively.

(3) In a manner similar to that described in Example 9-A, treat each ofthe 6-azido-11B-acetoxy-21-iodo-4,6- pregnadiene-3,20-diones prepared asdescribed in Example 8-C-2 with silver chloride in moist acetonitrile.Isolate each of the respective products in a manner similar to thatdescribed in Example 9A1 to obtain, respectively,

6-azido-9u-fluoro-2l-chloro-16a-methyl-4,6-pregnadiene-11B,17a-diol-3,20dione 1 l-acetate,

6-azido-9a-fiuoro-2l-chloro-l 6/3-methyl-4,6-pregnadiene- 115,17a-diol-3,20-dione ll-acetate,

6-azido-9a-fluoro-21-ch1oro-16-methylene-4,6-pregnadiene-l1B,17a-diol-3,20-dionell-acetate,

6-azido-9 a-fluoro-Z l-chloro l 6a,17a-isopropylidenedioxy-4,6-pregnadiene-l1;3-o1-3,20-dione ll-acetate, and

6-azido-21-chloro-4,6-pregnadiene-115,17a-diol-3 ,20-

dione ll-acetate.

(4) In the procedure of Example 9-A3 by using silver fluoride in placeof silver chloride there is obtained the corresponding 21-fluoroderivative of each of the products produced in Example 9-A-3.

(B) 6azido-9afluoro2l-halogeno-4,6-pregnadiene- 11,8,17a-diol-3,ZO-dione (1) In a manner similar to that described in Example 1-D,subject each of the 6-azido-1lfi-acetoxy-Zl-chloro-4,6-pregnadiene-3,20-diones prepared as described in Example 9-A-1 and9-A-3 to the action of the microorga- 34 nism Flavobacteriumdhydrogenans (ATCC 13930). Isolate and purify the resultant respectiveproducts in a manner similar to that described in Example l-D to obtain,respectively,

6-azido-9 a-fiuoro-2 1-chloro-4,6-pregnadiene-1 119,170:-

diol-3,20-dione,

6-azido-9a-fluoro-2l-chloro-l6a-methyl-4,6-pregnadiene-11fi,17a-diol-3,20-dione,

6-azido-9a-fluoro-2l-chloro-l6,8-methyl-4,6-pregnadiene-11B,17a-diol-3,20-dione,

6-azido-9u-fiuoro-21-chloro-l6-methylene-4,6-pregnadiene-l1B,17a-diol-3,20-dione,

6-azido-9u-fluoro-2l-chloro-16a,17u-isopropylidenedioxy-4,6-pregnadiene-11B-ol-3,20-dione, and

6-azido-2l-chloro-4,6-pregnadiene-115,17a-diol-3-20- dione.

(2) Similarly, in the manner described in Example l-D treat each of the6-azido-11B-acetoxy-21fluoro-4,6- pregnadiene-3,20-diones and 6-azido-113-acetoxy-21-bromo-4,6pregnadiene-3,20-diones prepared as described inExamples 9-A-2 and 9-A-4, to the action of the microorganism Flavobacterium dehydrogenans (ATCC 13930) and there will be obtained thecorresponding ll s-hydroxy derivative, e.g.6-azido-911,21-difiuoro-4,6-pregnadiene- 11 3,17u-diol-3,20'-dionell-acetate and 6-azido-9a-fiuoro- 21-bromo4,6-pregnadiene-11fl,17a-diol-3,20-dione ll-acetate.

EXAMPLE l0 6-azido-9a-fluoro-16a-methyl-4,6-pregnadiene-ll,8,17a,2ltriol-3,20-dione prepared via the ll-formate ester (A)6fi-aZido-9a-fluoro-16a-methyl-4-pregnene-7u,11p,17u,2l-tetrol-3,20-dione 11,17-dit'ormate 21-acetate (1) In a mannersimilar to that described in Example l-A, treat6a,7a-oxido-9a-fluoro-l6a-methyl-4-pregnene- 11fi,17a,21 triol3,20-dione 11,17-diformate 21-acetate with sodium azide in aqueousmethanol. Isolate and purify the resultant precipitate in a mannersimilar to that described to obtain6fi-azido-9a-fluoro-16u-methyl-4-pregnene 7a,llfi,l7ot,2ltetrol-3,20-dione 11,17-diformate 21-acetate.

(2) Similarly, treat each of 6u,7ot-0Xid0 9a-flu010- methyl 4pregnene-llfi,17a,21-triol-3,20-dione 11,17-diformate 2l-acetate and6a,7u-oxido-4-pregnenellB,17a,21 triol 3,20-dione 11,17-diformate2l-acetate with sodium azide in aqueous methanol. Isolate and purify theresultant product in a manner similar to that described hereinabove toobtain, respectively, 6j3-azido-9a-fiuoro- 16B methyl 4 pregnene70:,11,53,17oz,2l-tetro1-3,20 dione 11,17-diformate 21-acetate, and6fi-azido-4-pregnene 7u,llfi,l7oz,2l tetrol-3,20-dione 11,17-diformate21-acetate.

(B) 6fi-azido- 9m-fiuoro-16u-methyl-4-pregnene-7u,11p,17u,21-tetrol-3,20-dione 7,21-diacetate 11,17-diformate (1) In a mannersimilar to that described in Example 1-B, treat6B-azido-9a-fluoro16u-methyl-4-pregnene-17a, 11B,17a,21 tetrol-3,20dione 11,17-diformate 21-acetate with acetic anhydride in pyridine inthe presence of 4- dimethylaminopyridine. Isolate and purify theresultant product in a manner similar to that described to obtain 65azido 9a fiuoro-l6u-methyl-4-pregnene-7a,11,8, 17u,2l-tetrol-3,20-dione7,2l-diacetate 11,17-diforrnate.

(2) Similarly, treat each of the 6fl-azido-7a-hydroxy-4-pregnene-3,20-diones of Example 10-A-2 With acetic anhydride inpyridine in the presence of 4-dirnethylamino pyridine to yield thecorresponding 7-acetoxy derivative, i.e.6B-azido-9a-fiuoro-16B-rnethyl-4-pregnene-7a,113,17u, 21 tetrol 3,20dione 7,21-diacetate 11,17-diformate and 6,6 azido 4 pregnene-7tt,l1;f3,l7ot,2l-tetrol-3,20 dione 7,21-diacetate 11,17-diformate.

(C) 6-azido-9a-fiuoro-1'6a-methyl-4,6-pregnadiene-l1B-17a,21-triol-3,20-dione 11,17-diformate 2l-acetate In a manner similarto that described in Example 1-C, treat each of6B-azido-9a-fluoro-16a-methyl-4-pregnene- 7vz,l1}9,17a,21 tetrol 3,20dione 7,2l-diacetate 11,17- diformate and6B-azido-9a-fluoro-16fl-methyl-4-pregnene- 7a,11,B,17a,21 tetrol3,20-dione 7,21-diacetate 11,17-diformate with tetramethyl-ammoniumfluoride pentahydrate in acetonitrile. Isolate and purify the resultantproducts in a manner similar to that described to obtain 6- azido 9afluoro 16a-methyl-4,6-pregnadiene-115,170 21 triol 3,20-dione11,17-diformate 2l-acetate and 6- azido 9a fluoro16fl-methyl-4,6-pregnadiene-1113,17, 21-triol-3,20-dione 11,17-diformate21-acetate.

(D) To a solution of 1.6 g. of 6-azido-9a-fiuoro-l6umethyl 4,6pregnadiene 11B,l7a,2l-triol-3,20-dione 11,17-diformate 21-acetate in 60ml. of methanol, add 10 ml. of l-N-sodium hydroxide. Stir at roomtemperature overnight. Add acetic acid dropwise until the solutionreaches neutrality, then remove the solvent in vacuo. Extract theresultant residue with methylene chloride and wash the combined organicextracts with water. Dry over magnesium sulphate and evaporate themethylene chloride solution to a residue comprising6-aZldO90z-fll.lOIO-16amethyl 4,6 pregnadiene11,8,17u,21-tri0l-3,20-dione. Purify by chromatography.

(2) In similar manner, treat each of 6-azido-9a-fluoro- 16B methyl4,6-pregnadiene-11,3,l7a,2I-triol-3,20-dione 11,17-diformate 21-acetateand 6-azido-4,6-pregnadiene 11}3,17a,21 triol 3,20-dione 11,17-diformate21-acetate with sodium hydroxide in aqueous methanol to obtain,respectively, 6-azido-9a-fluoro-16fl-methyl-4,6-pregnadiene-11fl,l7cz,21 triol-3,20-dione and 6-azido-4,6-pregnadiene- 11B,17a,21-tri0l-3,20-di0ne.

EXAMPLE ll Conversion of 6a,7a-oxido-9m-fluoro-l6a-methyl-4-pregnenellfi,l7a,21 triol-3,20-dione ll-trifiuoroacetate 21 acetate to6-azido-9a-fluoro-16a-methyl-4,6-pregnadiene-llp,17a,21-triol 3,20-dione21-acetate via the ll-trifluoroacetate ester (A)6fl-azido-9a-fluoro-16a-methyl-4-pregnene-7a,1 1,8,17u,21-tetrol-3,20-dione ll-trifluoroacetate 21-acetate In a mannersimilar to that described in Example 2, treat 611,7 oxido9u-fluoro-16u-methyl-4-pregnene-l1B, 17a,2l-triol-3,20-dionell-trifiuoroacetate 21-acetate with sodium azide in aqueous methanol inthe presence of acetic acid. Isolate and purify the resultant product ina manner similar to that described to obtain 6fl-azido-9 tfiuoro 16ozmethyl 4-pregnene-7a,11fi,17a,21-tetr6l- 3,20-dione ll-trifiuoroacetateZI-acctate.

(B) 6fl-azido-9a-fluoro-16ot-methyl-4-pregnene-7a, 1 1,8,17a,2l-tetrol-3,20-dione 7,21-diacetate In a manner similar to thatdescribed in Preparation l-D-l, treat6/8-azido-9a-fiuoro-l6a-methy1-4-pregnene- 7a,11fl,174x,21 tetrol3,20-dione ll-trifluoroacetate 21- acetate with one molar equivalent ofacetic anhydride in pyridine. Isolate and purify the resultant productin a manner similar to that described to obtain 6-B-azido-9'afluoro 16o:methyl 4 pregnene 7a,11fi,17oc,2l-tet1'0l- 3,20-dione 7,21-diacetate.

(C) 6-azido-9a-fluoro-l6a-methyl-4,6-pregnadiene-1118,17a,21-triol-3,20-dione 21-acetate In a manner similar to thatdescribed in Example 1-C, treat 6B-azido 9afluoro-16a-methyl-4-pregnene-7a,11e, 17u,2l-tetrol-3,20-dione7,21-diacetate with tetramethylammonium fluoride pentahydrate inacetonitrile. Isolate and purify the resultant product in a mannersimilar to that described to obtain 6-azido-9a-fluoro-16m-methyl-4,6-pregnadiene-1 113,17a,21-triol-3,20-dione 2 l-acetate.

Alternatively, the compound of this example may be prepared according toprocedures described in following Examples 11D through 11G.

(D) 6fl-azido-9a-fluoro-16a-methyl-4-pregnene-7u,l 15,17a,21-tetrol-3,20-dione 7,11,21-triacetate (E) 6-azido-9a-fluoro-16a-methyl-4,6-pregnadiene-7u, 1 1,8,17a,2l-tetrol-3,20-dione11,21-diacetate In a manner similar to that described in Example l-C,treat 6B-azido 9a fluoro-1 6a-methyl-4-pregnene-7a,1118,17u,21-tetrol-3,20-dione 7,11,2l-triacetate with tetramethylammoniumfluoride in acetonitrile. Isolate and purify the resultant product in amanner similar to that described to obtain6-azido-9ot-fluoro-16a-methy1-4,6-pregnadiene-11,8,17a,21-triol-3,20-dione 11,21-diacetate.

(F) 6-azido-9u-fiuoro-16a-methyl-4,6-pregnadiene- 11B,l7a,21-triol-3,20-dione In a manner similar to that described inExample 1-D, subject 6 azido 9afluoro-16u-methyl-4,6-pregnadienel1,8,17a,21-triol-3,20-dione11,21-diacetate to the action of the microorganism Flavobacteriumdehydrogenans (ATCC 13930). Isolate and purify the resultant product ina manner similar to that described to obtain 6-azido- 9a-fluoro 16amethyl-4,6-pregnadiene-l1B,17a,21-triol- 3,20-dione.

(G) 6-azido-9u-fiuoro-16a-methyl-4,6-pregnadiene-11,B,17a,21-triol-3,20-dione 21-acetate In a manner similar to thatdescribed in Preparation 1-D-1, treat6-azido-9a-fluoro-16u-methyl-4,6-pregnadiene-l1B,17a,2l-triol-3,20-dionewith acetic anhydride in pyridine. Isolate and purify the resultantproduct in a. manner similar to that described to obtain6-azido-9ufiuoro 16a methyl 4, 6 pregnadiene-l1B,17a,2l-triol-3,20-dione 21-acetate.

EXAMPLE 12 6-azido-9ct-halogeno1,4,6-pregnatriene-l 113, l7a,21-

triol-3,20-dione (A) 6-azido-9u-halogeno-1,4,6-pregnatriene-1 1,6,17a,21-triol-3,20-dione 11,21-diacetates :Prepare a hydrochloricacid-dioxane solution by adding 4 0.5 ml. of concentrated hydrochloricacid and 5 ml. of

water to 49.5 ml. of dioxane. To 10 ml. of this hydrochloricacid-dioxane solution, add mg. of 6-azido-9afluoro 16oz methyl 4,6pregnadiene-llB,17a,21-triol- 3,20-dione 11,21-diacetate and mg. of2,3-dichloro- 5,6-dicyanobenzoquinone (DDQ). Under an atmosphere ofnitrogen warm the solution to 60 C. with stirring for 30 minutes. Pourthe reaction mixture into 100 ml. of water and extract with ethylaceate. Wash the combined ethyl acetate extracts with concentratedaqueous sodium sulfite solution and then with water. Dry the ethylacetate solution over magnesium sulphate and filter. Pass the solutionthrough a Florisil column, evaporate the eluate in vacuo to a residuecomprising 6-azido-9a-fluoro-16amethyl 1,4,6 pregnatriene 11]3,17u,21triol-3,20-dione 11,21-diacetate.

In similar manner, treat all the other6-azido-9a-halogeno-lLB-acetoxy-16-methyl4,6-pregnadienes prepared inExample 3-C with DDQ and concentrated hydrochloric acid and aqueousdioxane to obtain, respectively.

6-azido-9a-fiuoro-165-methyl-1,4,6-pregnatriene-1 15,

17a,2l-triol-3,20-dione, 11,21-diacetate.6-azido-9a-chloro-16a-methyl-1,4,6-pregnatriene-1 15,

17a,21-trio1-3,20-dione 11,21-diacetate,6-azido-9a-chloro-165-methyl-1,4,6-pregnatriene-115,

17a,21-triol-3,20-dione 1 1,21-diacetate,6-azido-9u-bromo-l6a-methyl-1,4,6-pregnatriene-l15,

171:,2 1-triol-3,20-dione 11,21-diacetate, and6-azido-9a-bromo-165-methyl-1,4,6-pregnatriene-l 15,

17a,21-triol-3,20-dione 1 1,21-diacetate.

(B) 6-azido-9a-halogeno-1,4,6-pregnatriene-1 15,17, 21-triol-3,20-dionesIn a manner similar to that described in Example 1D, subject each of the6-azido-9u-halogeno-1,4,6-pregnatriene 11,3,17a,21 triol-3,20-dione11,21-diacetates prepared in preceding Example 12-A to the action of themicroorganism Flavobacteriumdehydrogenans (ATCC 13930) to obtain,respectively,

We claim:

1. A compound selected from the group consisting of a 65 azido 7ozoxygenated 4 pregnene of following structural Formula I and thel-dehydro analogs thereof:

wherein Q is a member selected from the group consisting of hydroxy, ORwherein R is an acyl radical of a hydrocarboncarboxylic acid having upto 12 carbon atoms, and hydrogen provided W is a member selected fromgroup consisting of hydrogen and (H, lower alkyl);

V is a member selected from the group consisting of hydrogen and an acylradical of an acid selected from the group consisting of ahydrocarboncarboxylic acid having up to 8 carbon atoms and ahydrocarbonsulfonic acid having up to 7 carbon atoms;

W is a member selected from the group consisting of hydrogen, (H,loweralkyl), (H,a-hydroxy) and (H,a-OR') wherein R is an acyl radical of ahydrocarboncarboxylic acid having up to 12 carbon atoms, =CHT wherein Tis a member selected from the group consisting of hydrogen, lower alkyl,fluorine and chlorine, and W taken together with Q, 1601,1711- loweralkylidenedioxy;

X is a member selected from the group consisting of hydrogen and ahalogen having an atomic weight less than 100;

Y is a member selected from the group consisting of formyloxy, acetoxyand halogenoacetoxy; and

Z is a member selected from the group consisting of halogen, hydrogen,hydroxy, OR" wherein R is an 38 acyl radical of an acid selected fromthe group consisting of a hydrocarboncarboxylic acid having up to 12carbon atoms, and when taken together with Q, 17a,21-loweralkylidenedioxy.

2. A 65 azido 7a oxygenated 4 pregnene according to claim 1 wherein Y isa member selected from the group consisting of formyloxy, acetoxy andtrifluoroacetoxy.

3. A 65 azido 7a oxygenated 4 pregnene according to claim 1, Formula I,wherein X is a halogen having an atomic weight less than 100, and Y is amember selected from the group consisting of formyloxy, acetoxy andtrifluoroacetoxy.

4. A 65 azido 7oz oxygenated 4 pregnene ac cording to claim 1, FormulaI, wherein W is methylene and Y is a member selected from the groupconsisting of formyloxy, acetoxy and trifiuoroacetoxy.

5. A 65 azido 7o: oxygenated 4 pregnene according to claim 1, Formula I,wherein Q is hydroxy, V is hydrogen, W is a member selected from thegroup consisting of hydrogen and (H,lower alkyl), X is fluorine, Y isacetoxy and Z is OR", R" being lower alkanoyl, said compound having thefollowing structural formula:

I oHioR" 0:0

or-t3 I wherein R" and W are as hereinabove defined.

6. A compound according to claim 5 wherein W is (Ha-methyl) and R isacetyl, said compound being 65 azido 9oz fluoro 16a methyl 4 pregnene-704,115,17a,21-tetrol-3,20-dione 11,21-diacetate.

7. A compound according to claim 5 wherein W is (H,5-methyl) and R" isacetyl, said compound being 65 azido 9oz fluoro 165 methyl 4 pregnene-7oc,l 1 5,17u,21-tetrol-3 ,ZO-dione 11,21-diacetate.

8. A 65 azido 7a oxygenated 4 pregene according to claim 1, Formula I,wherein Q is hydroxy, V is lower alkanoyl, W is a member selected fromthe group consisting of hydrogen and (H,lower alkyl), X is fluorine andZ is OR", R" being lower alkanoyl, said compound having the followingstructural formula:

wherein R", V and W are as hereinabove defined.

9. A compound according to claim 8 wherein V and R" are acetyl and W is(Hm-methyl), said compound being 65 azido 9oz fluoro 16oz methyl 4pregnene- 70c,1 15,l7a,2ltetrol-3,20-dione 7,11,21-triacetate.

10. A compound according to claim 8 wherein V and R are acetyl and W is(H,5-methyl), said compound being 65 azido c fluoro methyl 4 pregnene-7a,1 l5,17u,21-tetrol-2,20-dione 7,11,21-triacetate.

11. A compound according to claim 1, Formula I, wherein Q is hydroxy, Vis hydroxy or the acetate ester thereof, W is methylene, X is fluorine,Y and Z are acetoxy, said compounds being 6,3 azido 90c fluoro l6-methylene 4 pregnene 7a,11fl,l7a,21 tetrol 3,20- dione 11,21-diacetateand the 7a-acetate ester thereof.

12. A compound according to claim 1, Formula I, wherein X is fluorine, Yand Z are acetoxy, and V is bydroxy or an acetate ester thereof, Q ishydroxy and W is acetoxy, or Q and W together are isopropylidenedioxy,said compounds being 65-azido-9a-fluoro-4-pregnene-7a,113,1611,l7a,2l-pentol-3,20-dione 11,16,2l-triacetate, and6fl-azido-9u-fluoro-l6a,l7a-isopropylidenedioxy 4pregnene-7m,l1fl,2l-triol-3,20-dione 11,2l-diacetate and the 7- acetateesters thereof.

13. A compound selected from the group consisting of a6-azido-4,6-pregnadiene-3,20-dione of following structural Formula I andthe l-dehydro analogs thereof:

wherein Q is a member selected from the group consisting of hydroxy, ORwherein R is an acyl radical of a hydrocarboncarboxylic acid having upto 12 carbon atoms, and hydrogen provided W is a member selected fromthe group consisting of hydrogen and (H,lower alkyl);

W is a member selected from the group consisting of hydrogen, (H,loweralkyl), (H,u-hydroxy) and (H,oc- OR) wherein R is an acyl radical of ahydrocarboncarboxylic acid having up to 12 carbon atoms, =CHT wherein Tis a member selected from the group consisting of hydrogen, lower alkyl,fluorine and chlorine, and W taken together with Q, 16a,17aloweralkylidenedioxy;

X is a member selected from the group consisting of hydrogen and ahalogen having an atomic weight less than 100;

Y is a member selected from the group consisting of formyloxy, acetoxyand halogenoacetoxy; and

Z is a member selected from the group consisting of hydrogen, halogen,hydroxy, OR" wherein R" is an acyl radical of an acid selected from thegroup consisting of a hydrocarbonsnlfonic acid having up to 7 carbonatoms and a hydrocarboncarboxylic acid having up to 12 carbon atoms, andwhen taken together with Q, 170:,21-10W6I alkylidenedioxy.

14. A 6-azido-4,6-pregnadiene-3,ZO-dione of claim 13 wherein Y is amember selected from the group consisting of formyloxy, acetoxy andtrifluoroacetoxy.

15. A 6-azido-4,6-pregnadiene-3,20-dione according to claim 13, FormulaI, wherein X is a halogen having an atomic weight less than 100, and Yis a member selected from the group consisting of formyloxy, acetoxy andtrifluoroacetoxy.

16. A 6-azido-4,6-pregnadiene-3,20-dione according to claim 13, FormulaI, wherein W is methylene and Y is a member selected from the groupconsisting of formyloxy, acetoxy and trifluoroacetoxy.

17. A 6-azido-4,6-pregnadiene-3,20-dione according to claim 13, FormulaI, wherein Q is hydroxy, W is a member selected from the groupconsisting of hydrogen and (H,lower alkyl), X is fluorine, Y is acetoxy,and Z is OR",

R" being lower alkanoyl, said compound having the following structuralformula:

CHzOR" wherein R" and W are as hereinabove defined.

18. A compound according to claim 17 wherein R" is acetyl and W is(Ha-methyl), said compounds being 6-azido-9a-fluoro-16a-methyl-4,6-pregnadiene 11fi,17a,21- triol-3,20-dione11,21-diacetate.

19. A 6-azido-4,6-pregnadiene according to claim 17 wherein Q ishydroxy, W' is (RB-methyl), and R" is acetyl, said compound being6-azido-9m-fluoro-l6fi-methyl-4,6-pregnadiene-l1B,17a,21-triol-3,20-dione11,21 diacetate.

20. A 6-azido-4,6-pregnadiene-3,ZO-dione according to claim 13, FormulaI, wherein Q is hydroxy, W and X are hydrogen, Y and Z are acetoxy, saidcompound being 6- azido-4,6-pregnadiene-llfl,17u,2l-triol 3,20 dione 11,ZI-diacetate.

21. A 6-azido-4,6-pregnadiene-3,ZO-dione according to claim 13, FormulaI, wherein Q is hydroxy, W is methylene, X is fluorine, Y and Z are eachacetoxy, said compound being 6-azido-9a-fluoro-16-methylene 4,6pregnadiene-l 1B,17u,2l-triol-3,20-dione 11,21-diacetate.

22. A 6-azido-4,6-pregnadiene-3,20-dione according to claim 13, FormulaI, wherein X is fluorine, Y and Z are each acetoxy, Q is hydroxy, and Wis acetoxy or, Q and W taken together are isopropylidenedioxy, saidcompounds being 6-azido-9a-fluoro-4,6-pregnadiene 115,160,l7a,2l-tetrol-3,20-dione 11,16,21-triacetate and 6-azido- 9afluoro-l6a,17ot-isopropylidenedioxy-4,6-pregnadiene- 1 113,21-diol-3,20-dione 11,2l-diacetate.

23. A process for preparing 6-azido-4,6-pregnadiene- 3,20-diones of thefollowing Formula I:

CHzZ

wherein Q is a member selected from the group consisting of hydroxy, ORwherein R is an acyl radical of a hydrocarboncarboxylic acid having upto 12 carbon atoms, and hydrogen provided W is a member selected fromthe group consisting of hydrogen and (H,lower alkyl);

W is a member selected from the group consisting of hydrogen, (H,loweralkyl), (H,a-hydroxy), (H,a- OR) wherein R is an acyl radical of ahydrocarboncarboxylic acid having up to 12 carbon atoms, =CHT wherein Tis a member selected from the group consisting of hydrogen, lower alkyl,fluorine and chlorine, and W taken together with Q, 16a,17aloweralkylidenedioxy;

X is a member selected from the group consisting of hydrogen and halogenhaving an atomic weight less than and

